WO1996002494A1 - Derives de benzocycloalcoylamine utiles comme antagonistes du canal a calcium - Google Patents

Derives de benzocycloalcoylamine utiles comme antagonistes du canal a calcium Download PDF

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Publication number
WO1996002494A1
WO1996002494A1 PCT/EP1995/002695 EP9502695W WO9602494A1 WO 1996002494 A1 WO1996002494 A1 WO 1996002494A1 EP 9502695 W EP9502695 W EP 9502695W WO 9602494 A1 WO9602494 A1 WO 9602494A1
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Prior art keywords
compound
formula
methyl
phenoxy
phenylethyl
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PCT/EP1995/002695
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English (en)
Inventor
Barry Sidney Orlek
John David Harling
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Smithkline Beecham Plc
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Filing date
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Priority claimed from GB9414184A external-priority patent/GB9414184D0/en
Priority claimed from GBGB9500688.8A external-priority patent/GB9500688D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU29825/95A priority Critical patent/AU2982595A/en
Publication of WO1996002494A1 publication Critical patent/WO1996002494A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to carbocylic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, in particular as calcium channel antagonists, e.g. for the treatment of ischaemia, in particular 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.
  • Ri is C1.3 alkylene
  • n and p are each inter alia zero
  • R2 and R3 represent inter alia hydrogen or lower alkyl
  • X is inter alia lower alkyl, lower alkoxy, CF3 or halogen
  • q is zero, 1 or 2.
  • the compounds are said to be useful as anudepressants and as inhibitors of synapdc norepinephrine and serotonin uptake.
  • EPA 371508 describes similar compounds and corresponding thiols, which compounds are said to be useful for the treatment of drug-resistant malaria and other drug-resistant protozoal infections.
  • X a represents O, S, NH
  • X D represents O, S, NH or a bond
  • p and q independently represent 0-4 such that the sum of p+q is at least 1
  • Ar represents phenyl optionally substituted by inter alia Ph(CH2) r Y(CH2) s - where Ph is optionally substituted phenyl, is oxygen or a bond and r and s each independently represent 0-4 provided that the sum of r+s is not greater than 4;
  • Rl and R ⁇ each independently represent hydrogen, Cj.galkyl, C3_6cycloalkyl or C ⁇ .4alkylC3.6Cycloalkyl; and n is 1,2 or 3.
  • n 1,2 or 3;
  • Rl and R ⁇ each independently represent hydrogen, C ⁇ _6alkyl, C3_6cycloalkyl, or C3_6 ⁇ ycloalkylC ⁇ _4alkyl;
  • p and q independently represent 0-4;
  • X represents O, S, NH or, provided that the sum of p and q is at least 1, a bond; and AT represents phenyl substituted by -Y-CR ⁇ R ⁇ -Ph, where Y is oxygen or a bond, R ⁇ and R ⁇ are independently, H, methyl or ethyl, provided that R ⁇ and R ⁇ are not both H, and Ph is optionally substituted phenyl; or a salt thereof.
  • Rl is hydrogen, methyl or isopropyl, particularly preferably methyl.
  • R ⁇ is hydrogen or methyl, particularly preferably hydrogen.
  • NR1R2 is preferably amino, methylamino or isopropylamino.
  • X is preferably O and p and q are 0, or X is a bond and the sum of p and q is 1.
  • n is preferably 1.
  • at least one of R ⁇ and R ⁇ is methyl. Particularly preferably R ⁇ and R ⁇ are both methyl; such compounds have good activity and have a minimal number of chiral centres.
  • Suitable substituents for the group Ph include halogen, especially fluorine, chlorine and bromine; Cj ⁇ alkoxy especially methoxy; Ci _4alkyl especially methyl; trifluoromethyl and trifluoromethoxy.
  • Particularly preferred substituents for Ph include 3-chloro, 3-fluoro, 4-chloro, 4-fluoro and 3,4-dichloro.
  • the substituent is at the 4- position of the phenyl group. Ph may advantageously be unsubstituted.
  • Alkyl groups present in the compounds of formula (I), alone or as part of another group, can be straight or branched.
  • a Cj.galkyl group may be for example methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl or any branched isomer thereof such as isopropyl or t-butyl.
  • Preferred meanings of C3_6cycloalkyl are cyclopropyl and cyclohexyl
  • preferred meanings of C3_6cycloalkylC ⁇ .4alkyl are cyclopropylmethyl and cyclohexylmethyl.
  • 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 final products and are included within the scope of this invention.
  • the compounds of formula (I) contain two 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.
  • the substituents on the carbocyclic (e.g. indane) nucleus may both lie on the same side with respect to the plane of the ring (cw-configuration) or on opposite sides (tr ⁇ ru-configuration). Both forms and all mixtures thereof are included within the scope of this invention.
  • the compounds of formula (I) are of the cw-configuration.
  • (+) and (-) designations used herein indicate the direction of rotation of plane-polarised light by the compounds.
  • the prefix (+) indicates that the isomer is dextrorotatory (which can also be designated d) and the prefix (-) indicates the levorotatory isomer (which can also be designated 1).
  • Particular compounds of the formula (I) include : ( ⁇ )cw- 1 -[4-(l -methyl- 1 -phenylethyl)phenoxy]-2-memylaminoindane ( ⁇ )cis- 1 -[4-( 1 -methyl- 1 -phenylethyl)phenoxy]-2-aminoindane ( ⁇ )cis- 1 - [4- ( 1 -methyl- 1 -phenylethyl)benzyl]-2-arninoindane (+) «..- 1 -[4-( 1 -methyl- 1 -phenylemyl)benzyl]-2-methyla ⁇ inoindane ( ⁇ )c ⁇ - 1 -[4-( 1 -methyl- 1 -(4-fluorophenyl)emyl)phenoxy]-2-a ⁇ noindane ( ⁇ ) s- 1 -[4-( 1 -methyl- 1 -(4-fluorophenyl)ethyl)phen
  • the compounds of the present invention can be prepared by processes analog to those known in the art.
  • the present invention therefore provides in a further aspect, process for the preparation of compounds of formula (I) which comprises : (a) to prepare a compound of formula (I) wherein R ⁇ is methyl, reduction of a compound of formula (II)
  • n, p, q, R , Ar and X are as hereinbefore defined and Alk is a C ⁇ _4alkyl group;
  • n, q, X and Ar are as hereinbefore defined and R ⁇ is hydrogen, C ⁇ _4alkyl or phenylC ⁇ _4alkyl (e.g. benzyl);
  • Rl, R ⁇ , p and n are as hereinbefore defined and X* is O, S or NH, with a compound of formula L(CH2)qAr wherein L is a leaving group and q and Ar are as hereinbefore defined;
  • Rl, R ⁇ , p and n are as hereinbefore defined and L is a group displaceable by a nucleophile, with a compound HX(CH2) Ar wherein X, q and Ar are as hereinbefore defined;
  • R 1 and R 2 are both hydrogen, conversion to a compound of formul (I) where at least one of R 1 and R 2 represent alkyl; and optionally after any of the above processes: separation of enantiomers and/or forming a salt of formula (I).
  • Reduction according to process (a) may be effected using a suitable reducing agent such as lithium aluminium hydride, preferably in an inert solvent such as tetrahydrofuran or diethyl ether.
  • a suitable reducing agent such as lithium aluminium hydride
  • an inert solvent such as tetrahydrofuran or diethyl ether.
  • Alk in formula (II) represents tert- butoxycarbonyl the process is preferably carried out in tetrahydrofuran at reflux.
  • Deprotection according to process (b) may be carried out by conventional methods.
  • an ethoxycarbonyl group may be removed by hydrolysis under basic conditions.
  • a t -butoxycarbonyl group may be cleaved using trifluoroacetic acid, in a solvent such as dichloromethane.
  • Reduction of a compound of formula (HI) according to process (c) may be effected using a reducing agent such as lithium aluminium hydride or NaBH3(OCOC in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran.
  • a reducing agent such as lithium aluminium hydride or NaBH3(OCOC in an inert solvent such as an ether, e.g. diethyl ether or tetrahydrofuran.
  • the process may be carried out using lithium or sodium borohydride in combination w tnmethylsilyl chloride, in tetrahydrofuran. In general this process gives predominantl the ⁇ s-form of the product.
  • R ⁇ is Cj ⁇ alkyl.
  • the reaction between a compound of formula (IV) and L(CH2)qAr may be effected under conditions which depend on the nature of L and th value of q.
  • L is preferably fluoro 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.
  • the reaction between a compound of formula (V) and HX(CH2)qAr in process (e) can take place under conditions which depend on the nature of L ⁇ and X.
  • L* is hydroxy
  • X is oxygen or sulphur
  • q is 0
  • the reaction is carried out in the presence of diethyl azodicarboxylate and triphenyl phosphine.
  • the leaving group L 1 may be for example a halogen atom or a sulphonyloxy group eg.
  • reaction may be effected using standard conditions, in the presence or absence of solvent, optionally in the presence of a base. It will be appreciated by the skilled worker that it may be necessary to use a suitable N-protecting group to control the stereochemical outcome of this process.
  • Interconversion s according to process (g) may be effected by alkylation of a compound (I) wherein one of R* and R 2 is hydrogen and the other is alkyl or where R* and R 2 are both hydrogen, using an appropriate alkylating agent such as an alkyl halide e.g. an alkyl bromide or iodide, in the presence of a base, such as potassium carbonate.
  • an appropriate alkylating agent such as an alkyl halide e.g. an alkyl bromide or iodide
  • a base such as potassium carbonate.
  • the reaction may be carried out in a suitable solvent such as acetone.
  • said compound of formula (I) may first be acylated, using for example an alkylhaloformate such as ethyl chloroformate, preferably in the presence of a tertiary amine such as triethylamine, or a carbonate such as di-t -butyldicarbonate, in the presence of sodium hydroxide and a solvent such as dioxane, to provide a compound of formula (II) followed by reduction as described above.
  • a compound of formula (I) may be subjected to reductive alkylation using an appropriate aldehyde (e.g. formaldehyde) or ketone, and a reducing agent such as sodium cyanoborohydride.
  • a compound of formula HXAr may be prepared from a compound HXAr ⁇ (wherein Ar* is phenyl substituted by optionally substituted benzoyl) or a derivative thereof e.g. the corresponding methyl ether, according to the method of process (f) described hereinabove, followed where necessary by cleavage of the ether using trimethylsilyl iodide.
  • a rr ⁇ /is-isomer of formula (II) wherein R is hydrogen and Alk is t -butyl may be prepared by reaction of a compound of formula (V1T) with a Grignard derivativ of formula L 2 Mg(CH2)pX(CH2)qAr, wherein L 2 is halo.
  • X is preferably a bond.
  • the reaction is conveniently effected in the presence of copper (I) bromide dimethylsulphide complex and in a solvent such as toluene.
  • the Grignard derivative may be prepared using standard procedures from a corresponding compound of formula L 2 (CH2)pX(CH2)qAr, optionally in situ.
  • a compound of formula (VII) may be prepared by cyclisation of a compound of formula (V ⁇ l) :
  • Formula (VHI) using sodium hydride in a suitable solvent for example an ether such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5; or dimethyl formamide.
  • a suitable solvent for example an ether such as tetrahydrofuran optionally containing a crown ether such as 15-crown-5; or dimethyl formamide.
  • a compound of formula (IX) is commercially available or can be prepared according to known methods.
  • a compound of formula (Ul) may be prepared by reaction of a compound of formula (X):
  • (X) may be prepared using methods known in the literature.
  • TrflrU-isomers of formula (IV) wherein X* is oxygen and p is zero may be prepared as described in the literature e.g. Chem. Pharm. Bull. 1977, 25, 1060.
  • Corresponding cw-isomers may be obtained by oxidation of the tr ⁇ /ts-isomer using Jones reagent to give a ketone followed by reduction with lithium tri-O-isobutyl borohydride (L-Selectride®, Aldrich). Reduction of the ketone using sodium borohydride regener the tr ⁇ / ⁇ s-isomer.
  • Compounds of formula (IV) wherein X 1 is S or NH may be prepared from th corresponding sulphonyloxy compound e.g. a mesylate and an appropriate amino or th reagent using standard methods.
  • the sulphonyloxy derivative may itself be prepared from the corresponding alcohol in conventional manner.
  • a compound of formula (XI) can be converted into a compound of formula (XII) for example by heating under reflux in chloroform, and the product can be alkylated e.g. by reaction with an alkyl halide and sodium hydride in a suitable dipolar aprotic solvent.
  • the compound (XI) may be prepared by reaction of the corresponding indene of formula (IX) with N,N-dichloro-terr-butylcarbamate
  • the compounds of formula (XIII) can be reduced by lithium aluminium hydri to give compounds of formula (IV) in which R 2 is methyl.
  • Compounds of formula (X or (XIII) can be treated with sodium hydroxide to give compounds of formula (IV) in which R 2 is hydrogen.
  • Compounds of formula (IV) in which R* is methyl and R 2 is hydrogen can be prepared by reducing an oxazoline of formula (XV) e.g. with lithium aluminium hydride, which can be prepared from a compound of formula (XIV):
  • Compounds of formula (VI) may be prepared using processes analagous to (a) to (g) described above, advantageously by reaction of a compound of formula (IV) with a compound L(CH2)qAr ⁇ where Ar ⁇ is phenyl substituted by optionally substituted benzoyl according to process (d).
  • 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 compounds of formula (I) are resolved by conversion to a mixture of diastereomeric amides, which are separated by conventional methods and then reconverted into resolved compounds of formula (I).
  • the amides are formed with S(+)- ⁇ -methoxyphenylacetic acid, and the separated amides can be converted into the resolved amines by treatment with an excess of methyllithium, or by treatment with an excess of potassium t-butoxide in wet tetrahydrofuran as generally described in U.S. 5,149,714.
  • An ischaemic event such as stroke results in disruption of the blood supply to the brain, depriving it of essential oxygen and glucose.
  • a cascade of biochemical reactions ensues, a consequence of which is to permit the influx of calcium ions into the brain cells (neurons) via so-called Voltage Operated Calcium Channels (VOCCs) causing cell death.
  • VOCCs Voltage Operated Calcium Channels
  • agents which inhibit such calcium influx will minimise cell death and hence increase the potential for recovery.
  • Compounds of formula (I) have been found to exhibit high calcium influx blocking activity, for example in neurons.
  • the compounds may thus be referred to as neuronal calcium antagonists.
  • 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 ischaemia, including for example stroke; anoxia, due to causes including cardiac arrest, and cardiac surgery; and traumatic head injury. They may also be of use in the treatment of migraine; pain; epilepsy; ATDS-related dementia; neuro- degenerative diseases, such as Alzheimer's disease and age-related memory disorders; mood disorders; and drug addiction withdrawal such as ethanol addiction withdrawal.
  • 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) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treatment of ischaemia including for example stroke, anoxia or traumatic head injury 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 invention also provides a method of treatment of migraine, pain, epilepsy, 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 present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition or disease related to the accumulation of calcium in the brain cells of a mammal.
  • Compounds of the present invention will preferably be of use in the treatment of ischaemic stroke.
  • a preferred compound for use according to the invention is (+) cis-l-[4- (1 -methyl- 1 -phenylethyl)phenoxy]-2-methylaminoindane and salts thereof.
  • the compounds of formula (I) are usually administered in a standard pharmaceutical composition.
  • the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the compounds of formula (I) may be administered by any convenient method for example by oral, parenteral, buccal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
  • 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 carriers), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • suitable pharmaceutical carriers 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.
  • 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 cyclodextrins.
  • 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 m (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compou 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 do of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g.
  • the compounds of t invention may be administered by continuous intravenous infusion, preferably at a dos of up to 400 mg per day.
  • the total daily dosage by oral administration will be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will be i the range 0.1 to 400 mg.
  • the compounds will 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 NMD A 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 NMD A antagonists
  • a free radical inhibitor such as a free radical inhibitor
  • a calpain inhibitor a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • Superior cervical ganglion neurons were isolated and cultured following a meth modified from Marrion et al, Neurosci. Lett., 77, 55-60 (1987). Cells were plated on laminin coated plastic tissue culture dishes and incubated at 37°C until just prior recording. Electrophysiological recordings were performed from 2 to 9 days aft dissociation.
  • the pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 1 MgCl2, 4; ATP, 2; buffered to pH 7.2 with CsOH.
  • Cells were bathed in a norm 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-Cl, 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.
  • mice Male Mongolian gerbils weighing between 60-80 g were anaesthetised with halothane, placed on a heated mat and the carotid arteries occluded for 6 min. After reperfusion, the animals were sutured and placed in an incubator for 2 hours to maintain body temperature during the acute recovery phase. The animals were then caged separately and on the 5th day after the day of surgery, they were assessed for locomotor activity using an automated locomotor activity monitoring system and were then euthanased and the brains removed for histological analysis. The dosing protocol in these experiments was lOmg.kg" 1 30 minutes post-ischaemia then 3 mg.kg" 1 b.i.d. for 3 days. Injections were given via the i.p. route, the vehicle was distilled water.
  • test compound produced a significant reversal of the histological damage in the CA1 region of the hippocampus compared with that seen in the ischaemic vehicle-treated animals, and produced a significant reversal of the ischaemia- induced hyperlocomotion.
  • mice weighing 25-29g were anaesthetised with tribromoethanol, placed on a heat-pad and the mid-cerebral artery cauterised and divided via the intra-cranial route. On completion of surgery the mice were placed in an incubator for 2 hours to maintain body temperature during the acute recovery phase. On the 4th day the mice were euthanased and the brains removed for histological analysis. The dosing protocol in these experiments was lOmg.kg *1 30 minutes post-ischaemia then lOmg.kg" 1 b.i.d. for 3 days. Injections were given via the i.p. route, and the vehicle was 10% HPCD (hydroxypropyl- ⁇ - cyclodextrin).
  • test compound produced a significant reversal of the histological damage in the cerebral cortex as seen in the ischaemic vehicle-treated animals.
  • Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
  • Solvent Typically water but may also include cyclodextrins, e.g. hydroxypropyl- ⁇ - cyclodextrin (1-100 mg) and co-solvents such as propylene glycol, polyethylene glycol and alcohol. Tablet
  • Diluent e.g. Microcrystalline cellulose, lactose, starch Binder : e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
  • Disintegrant e.g. Sodium starch glycoUate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
  • 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
  • the invention is further illustrated by the following non-limiting Preparations and Examples:
  • (+) N-t -butoxycarbonyl-l,2-iminoindane as a brown solid (12.67g).
  • the faster eluting diastereomer (1.97g, 3.9mmol) was dissolved in dry tetrahydrofuran (120ml) and treated with potassium r -butoxide (19.7g), and water (0.330ml). The mixture was then stirred vigorously for 90 minutes. . After filtering off the solid material, the mixture was poured into water (400ml) and extracted with diethyl ether (3 x 100ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I), dans laquelle n vaut 1, 2 ou 3; R1 et R2 désignent indépendamment hydrogène, alcoyle C¿1-6?, cycloalcoyle C3-6 ou alcoyle C1-4 cycloalcoyle C3-6; p et q représentent indépendamment 0 à 4; X désigne O, S, NH ou une liaison, à condition que la somme de p et q soit au moins 1; et Ar désigne phényle substitué par -Y-CR?3R4¿-Ph, où Y désigne oxygène ou une liaison; R3 et R4 désignent indépendamment l'un de l'autre H, méthyle ou éthyle, à condition que R3 et R4 ne désignent pas tous les deux H; et Ph représente phényle éventuellement substitué. Ces composés et leurs sels constituent des antagonistes du canal à calcium utiles dans le traitement d'états ischémiques tels que l'apoplexie.
PCT/EP1995/002695 1994-07-14 1995-07-10 Derives de benzocycloalcoylamine utiles comme antagonistes du canal a calcium WO1996002494A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29825/95A AU2982595A (en) 1994-07-14 1995-07-10 Benzocycloalkylamine derivatives as calcium chanel antagonists

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
GB9414184A GB9414184D0 (en) 1994-07-14 1994-07-14 Compounds
GB9414184.3 1994-07-14
GBGB9500688.8A GB9500688D0 (en) 1995-01-13 1995-01-13 Compounds
GB9500688.8 1995-01-13
US45577695A 1995-05-31 1995-05-31
US45581295A 1995-05-31 1995-05-31
US08/455,812 1995-05-31
US08/455,776 1995-05-31

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US6166052A (en) * 1998-03-11 2000-12-26 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6251919B1 (en) 1998-02-27 2001-06-26 Warner-Lambert Heterocyclic substituted aniline calcium channel blockers
WO2010025856A1 (fr) * 2008-09-02 2010-03-11 Sanofi-Aventis Aminoindanes substitués, leurs analogues, et leur utilisation pharmaceutique

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EP0303961A2 (fr) * 1987-08-14 1989-02-22 Merrell Dow Pharmaceuticals Inc. Antidépresseurs
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995004027A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Aminoindanes et composes apparentes utiles comme antagonistes des canaux a calcium
WO1995004028A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Derives d'indane et de tetrahydronaphtalene a titre d'antagonistes des canaux a calcium

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EP0303961A2 (fr) * 1987-08-14 1989-02-22 Merrell Dow Pharmaceuticals Inc. Antidépresseurs
WO1994013291A1 (fr) * 1992-12-15 1994-06-23 Smithkline Beecham Plc Utilisation d'amines cycliques a substitution aryloxyalkyle comme antagonistes des canaux a calcium et nouveaux derives de piperidine phenyloxyalkyle
WO1995004027A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Aminoindanes et composes apparentes utiles comme antagonistes des canaux a calcium
WO1995004028A1 (fr) * 1993-07-28 1995-02-09 Smithkline Beecham Plc Derives d'indane et de tetrahydronaphtalene a titre d'antagonistes des canaux a calcium

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US6469038B1 (en) 1998-03-11 2002-10-22 Warner-Lambert Company Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
US6989448B2 (en) 1998-03-11 2006-01-24 Lain-Yen Hu Heteroaryl alkyl alpha substituted peptidylamine calcium channel blockers
WO2010025856A1 (fr) * 2008-09-02 2010-03-11 Sanofi-Aventis Aminoindanes substitués, leurs analogues, et leur utilisation pharmaceutique
CN102203059A (zh) * 2008-09-02 2011-09-28 赛诺菲-安万特 取代的氨基茚满及其类似物以及其医药用途
CN103396402A (zh) * 2008-09-02 2013-11-20 赛诺菲-安万特 取代的氨基茚满及其类似物以及其医药用途
US8822449B2 (en) 2008-09-02 2014-09-02 Sanofi Substituted aminoindanes and analogs thereof, and the pharmaceutical use thereof
CN102203059B (zh) * 2008-09-02 2015-05-06 赛诺菲-安万特 取代的氨基茚满及其类似物以及其医药用途
US9550788B2 (en) 2008-09-02 2017-01-24 Sanofi Substituted aminoindanes and analogs thereof, and the pharmaceutical use thereof

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