EP0673248A1 - Activateurs des vannes a potassium utilises en therapie - Google Patents

Activateurs des vannes a potassium utilises en therapie

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Publication number
EP0673248A1
EP0673248A1 EP94902046A EP94902046A EP0673248A1 EP 0673248 A1 EP0673248 A1 EP 0673248A1 EP 94902046 A EP94902046 A EP 94902046A EP 94902046 A EP94902046 A EP 94902046A EP 0673248 A1 EP0673248 A1 EP 0673248A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
pharmaceutical composition
use according
group
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.)
Withdrawn
Application number
EP94902046A
Other languages
German (de)
English (en)
Inventor
Kuok Keong Smithkline Beecham Pharmacs. Vong
John Morris Smithkline Beecham Pharmacs. Evans
Guy M.M.G. Smithkline Beecham Lab.Pharma Nadler
Robert Nicholas Willette
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Ltd
SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd, SmithKline Beecham Corp filed Critical SmithKline Beecham Ltd
Publication of EP0673248A1 publication Critical patent/EP0673248A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—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

Definitions

  • EP Published Patent Application No. 0126311 discloses substituted benzopyran compounds having blood pressure lowering activity, including 6-acetyl- trans-4-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3-ol. Also EP-A-0 376524, EP-A-0 205 292, EP-A-O 250 077, EP-A-0093 535, EP-A-0 150 202, EP-A-0076075 and WO/89/05808 (Beecham Group pic) describe certain benzopyran derivatives which possess anti-hypertensive activity.
  • EP-A-0 430 621 and EP-A-0 385 584 (Beecham Group pic) describe the resolution of certain intermediates useful in the preparation of the compounds described in the above mentioned patent applications.
  • EP-A-0 194 885 (E. Lilly) describes certain amino substituted benzopyran derivatives possessing anti-convulsant activity.
  • PCT/GB92/01045 (SmithKline Beecham pic; unpublished at the priority date), which describes certain fluorobenzoylamido benzopyrans, pyranopyridines and tetrahydronaphthylenes in which the 3 and 4 position substituents are trans to each other. These compounds are described as possessing inter alia anxiolytic and anti- convulsant activity.
  • the present invention provides a method of treatment and/or prophylaxis of anxiety, mania, depression, 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; and in the treatment or prevention of cerebral ischaemia, disorders resulting from sub- arrachnoid haemorrhage, Parkinson's Disease, migraine and/or psychosis, comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I) or pharmaceutically acceptable salt thereof:
  • P is a ring system selected from the following: a)
  • J is carbon and M is nitrogen and J a and M a are hydrogen;
  • Rj and R2 are hydrogen and the other is selected from the class of hydrogen, C3_g cycloalkyl, C ⁇ . alkyl optionally interrupted by oxygen or substituted by hydroxy, Ci _g alkoxy or substituted aminocarbonyl, C . alkylcarbonyl, Ci .5 alkoxycarbonyl, C ⁇ .
  • alkylcarbonyloxy C g alkoxy, nitro, cyano, halo, trifluoromethyl, CF3S, or a group CF3-A-, where A is -CF2-, -CO-, -CH2-, CH(OH), SO2, SO, CH2-O, or CONH, or a group CF2H-A'- where A' is oxygen, sulphur, SO, SO2, CF2 or CFH; tri luoromethoxy, C ⁇ g alkylsulphinyl, perfluoro C2-6 alkylsulphonyl, Cj.g alkylsulphonyl, C ⁇ _6 alkoxysulphinyl, C j .g alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl
  • alkylcarbonylamino C ⁇ _6 alkoxycarbonylamino, Cj.g alkyl-thiocarbonyl, C . alkoxy-thiocarbonyl, C j .6 alkyl-thiocarbonyloxy, 1-mercapto C2.7 alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, any amino moiety being optionally substituted by one or two C1 _ ⁇ alkyl groups, or C ⁇ . alkylsulphinylamino, C ⁇ _ - alkylsulphonylamino,C ⁇ _6 alkoxysulphinylamino or C ⁇ .
  • R7 is heteroaryl or phenyl; both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by Cj_4 alkyl, cyano, azido, C1.4 alkyl, C ⁇ _4 alkoxy, trifluoromethoxy and trifluoromethyl;
  • Rg is hydrogen; C ⁇ . alkyl, OR9 or NHCORJO wherein R9 is hydrogen, C ⁇ _6 alkyl, formyl, C ⁇ . alkanoyl, aroyl or aryl-C ⁇ 6 alkyl and Rio is hydrogen, C ⁇ _6 alkyl, C ⁇ . alkoxy, mono or di C ⁇ .
  • All Cj.g alkyl or C 1.4 alkyl or alkyl containing groups in formula (I) are preferably selected from methyl, ethyl, n - and iso -propyl, n -, iso -, sec - and tert-butyl.
  • Suitable C3_g cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Suitable halo substituents include fluoro, chloro and bromo.
  • Aryl whenever mentioned herein includes but is not limited to phenyl and naphthyl.
  • Heteroaryl whenever mentioned herein includes a 5- or 6- membered monocyclic or 9- or 10- membered bicyclic of which 5- or 6- membered monocyclic heteroaryl is preferred.
  • 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl preferably contains one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur and which, in the case of there being more than one heteroatom, are the same or different.
  • Examples of 5- or 6-membered monocyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl and thiadiazolyl, and pyridyl, pyridazyl, pyrimidyl, pyrazolyl and triazolyl.
  • Preferred examples of such groups include furanyl, thienyl, pyrryl and pyridyl, in particular 2- and 3-furyl, 2- and 3-pyrryl, 2- and 3-thienyl, and 2-, 3- and 4-pyridyl.
  • 9- or 10-membered bicyclic heteroaryl containing one, two or three heteroatoms which are selected from the class of oxygen, nitrogen and sulphur include benzofuranyl, benzothienyl, indolyl and indazolyl, quinolyl and isoquinolyl, and quinazolyl.
  • Preferred examples of such groups include 2- and 3-benzofuryl, 2- and 3-benzothienyl, and 2- and 3-indolyl, and 2- and 3-quinolyl.
  • the thienophene moiety is preferably i).
  • R, and R ⁇ are preferable both hydrogen or R, is nitro and R « is hydrogen.
  • R- and R. are preferably both methyl.
  • R- is hydroxy
  • R fi is hydrogen and R Q is hydrogen.
  • R ⁇ is hydrogen.
  • R j ,NCOR 7 group is trans to the Re group.
  • R*. is preferably cyano or nitro.
  • R- and R . are preferably both hydrogen or both methyl.
  • R ⁇ - is hydroxy
  • R fi is hydrogen and R Q is hydrogen.
  • R ⁇ is hydrogen.
  • the RoNCOR- group is trans to the R e ⁇ group.
  • R7 is phenyl optionally independently substituted; this includes substitution by 1,2,3,4 or 5 groups or atoms attached to the phenyl ring.
  • the groups or atoms may be in any position around the phenyl ring.
  • R7 is heteroaryl optionally independently substituted; this includes substituents at any vacant positions around the heteroaryl moiety.
  • R7 is fluorophenyl. More preferably R7 is mono-fluorophenyl and even more preferably R7 is 2-, 3 or 4-fluorophenyl. Most preferably R7 is 4- fluorophenyl.
  • the compounds of formula (I) may have chiral carbon atoms at positions around the saturated portion of ring system P especially at the atoms attached to R5 and the moiety Rg NCOR7 and therefore may exist as enantiomers.
  • the present invention extends to each enantiomer and to mixtures thereof including racemates.
  • R substituents also have chiral centres and therefore may exist as enantiomers.
  • the present invention extends to each enantiomer and to mixtures thereof including racemates
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof also includes solvates of such compounds, such as for example the hydrate.
  • the administration to the mammal may be by way of oral or parenteral administration.
  • An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal.
  • 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.
  • a unit-dose composition such as a unit dose oral, 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, colourants, 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.
  • 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 /. -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 prophylaxis of anxiety, mania, depression, disorders associated with a subarachnoid haemorrhage, neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression and/or disorders associated with a subarachnoid haemorrhage, neural shock the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines; disorders treatable or preventable with anti-convulsive agents, such as epilepsy; Parkinson's disease, psychosis, migraine and/or cerebral ischaemia.
  • compositions may be prepared in the manner as hereinbefore described.
  • the invention also extends to novel compounds of formula (I) and pharmaceutically acceptable salts thereof.
  • novel compounds are: rr ⁇ i_'-3-cyano-5-(4-fluorobenzamido)-6,7,8,9-tetrahydro-5H-benzocycloheptan-6-ol and rr ⁇ /w-7-cyano-5-(4-fluoroben__ami__o)-4-hydroxy-2,2-dimethyl-2,3,4,5-tetrahydro-l- benzoxepine.
  • compounds of formula (I) which have trans isomerisation between the groups attached to the atom attached to the group Rg NCOR7 and the group attached to the atom adjacent, on the right-hand side of the diagram as shown herein may be prepared by procedures generally described or analogous to those described in EP-0126311, EP-0376524, EP-205292, EP-0250077, EP-0093535, EP-0150202, EP-0076075, WO/89/05808, EP-0350805, EP-0277611, EP-0277612, EP-0337179, EP-0355565, EP-A-0482934, EP-A-0296975, JO-2004- 791 WO ⁇ 89 ⁇ l 1477and WO ⁇ 89 ⁇ 07103 EP-0466131, EP-A-0489300, DE 3,831,697, EP-A-0432893 and DE 4,010,488.
  • compounds of formula (I) which have cjs isomeration between the groups attached to the atom attached to the group RgNCOR7 and the group attached to the atom adjacent on the right-hand side of the diafrom as shown herein may be prepared according to the procedures generally described on or analogous to those described in EP-A-0139992.
  • Cis compound of formula (I) may also be prepared according to the procedures described by G. Burrell et al, Tet. Letters, 21, 3649-3652 (1996) or by the procedures described by U. Quast and E. Villhauer, Eur. J. Pharmacol, Molecular Pharmacology Section 245, 165-171 (1993). It should be appreciated that racemates for formula (I) may be resolved or enantiomerically purified compounds of formula (I) may be prepared using procedures conventional in the art and in particular using the procedures outlined in EP-0430631 and EP-0355584.
  • the compounds of formula (I) may be prepared in the required enantiomeric form by forming a chirally pure epoxide using catalysts and conditions generally outlined in WO91M4694 or WO 93M7026 and thereafter converted to the required compound of formula (I) using procedures outlined herein.
  • the invention also provides the use of novel compounds of formula (I), or a pharmaceutically acceptable salt thereof as a therapeutic agent, in particular in the treatment and/or prophylaxis of anxiety, mania, depression, 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; cerebral ischaemia disorders resulting from subarachnoid haemorrhage, Parkinson's disease, migraine and/or psychosis.
  • the following compounds were prepared by methods analgous to those described in the abovementioned patents publications.
  • Bromobenzene (90 ml) and ⁇ -carbomethoxybutyroyl chloride (28g) were mixed together under N2 and AICI3 (47 g) was added in small portions maintaining the temperature between 5- 10°C.
  • reaction mixture was allowed to reach room temperature and then heated at 100°C for 2 hours, then poured into a mixture of ice and 37% HC1 (55ml) and extracted with EtOAc three times. The combined organic phases were washed with water, brine, dried and concentrated to give a crude product as an oil (42g).
  • This compound was prepared as described in Example 2 of PCT ⁇ GB89 ⁇ 00588.
  • This compound was prepared from the corresponding epoxide which was prepared as described by Buckle et al, J. Chem. Soc. Perkin I (1991) 2763-2771, and thereafter forming the 5-amino, 4-alcohol and coupling with 4-fluorobenzoyl chloride using conventional procedures. p 199-201°C.
  • Rat Social Interaction Test The compounds of formula (I) or pharmaceutically acceptable salts thereof are tested for therapeutic utility using the procedure outlined as follows:
  • mice Male Sprague - Dawley rats (Charles River, U.K., 250 - 300g) are singly housed for 3 days prior to testing. On the test day, the animals are then randomly assigned to groups of 8 - 16 and dosed orally at a dose volume of 1 ml/kg with various doses of compound (1 - 300 mg/kg) or vehicle. At 60 min post dose the rats are placed with a weight - and treatment - matched pair male (encountered for the first time) in the social interaction box under high - light, unfamiliar conditions. The box is made of white perspex 54 x 37 x 26 cm with a transparent perspex front side. The floor is divided into 24 equal squares and is brightly lit (115 lux).
  • Time spent (sees) in active social interaction is scored "blind” by remote monitoring as is the number of squares crossed (as an index of locomotion).
  • the mean and standard error for time spent in social interaction and number of squares crossed are then calculated for each particular treatment group and drug - induced changes are expressed as a percentage increase or decrease from control values.
  • Statistical comparisons are made between vehicle - and drug - treated groups using Dunnett's multiple comparisons procedure following significant one way analysis of varience.
  • the maximal electroshock seizure (MES) 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 Male, Charles River, U.K. CD - 1 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 'up and down' method of Dixon and Mood (1948) 2 . Stastical comparisons between vehicle - and drug - treated groups are made using the method of Litchfield and Wilcoxon (1949) 3 .
  • the CC50 In control animals the CC50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested. The percentage increase or decrease in CC50 for each group compared to the control is calculated. Studies are carried out using a Hugo Sachs Electronik Constant Current Shock
  • Drugs are suspended in 1% methyl cellulose.
  • the compound of example 2 enhanced the threshold of shock by 95% at 30 mg kg p.o.
  • the X-maze test of anxiety examines the exploratory response of naive rats in an environment which offers both anxiogenic (open arms) and relatively non-anxiogenic (closed arms) areas. A selective increase in exploration of the open arms following drug pretreatment is therefore postulated to indicate anxiolytic effects.
  • the X-maze was raised 70cm above the floor and consisted of two enclosed arms 45cm (long) x 15cm (wide) x 10cm (high) and two open arms 45 x 10 x 1cm arranged such that the two arms of each type were opposite each other. Both arm types were marked into two equal sections. Rats were placed onto the centre of the X-maze and observed for a period of 10 minutes during which time the following parameters were recorded: 1) the number of entries onto, and the time spent on, (a) open arms, (b) closed arms, (c) end of open arms and (d) end of closed arms. 2) the number of sections crossed. The fear-drive evoked in the open arms exceeds that in the enclosed arms and rats typically show a clear preference for the enclosed arms.
  • Anxiolytic drugs increase the number of entries made onto, and the time spent on, the outer half of the open arms, and also the percentage of entries made onto, and the time spent on, the whole of the open arms. These four measures of anxiety, and also the total number of sections traversed, were calculated for each animal. Drugs are administered intraperitoneally or orally to groups of 6 to 12 rats 30 to 60 mins before testing. Statistical comparisons between vehicle- and drug-treated groups were made using a Mann- Whitney 'U' test (two tailed).
  • End-tidal CO2 (et CO2) is monitored continuously and arterial blood gas analysis was performed periodically to assure stable and adequate ventilation throughout each experiment.
  • Polyethylene cannulae are placed in the left external jugular vein and the right femoral artery and vein for drug administration, monitoring arterial blood pressure, and blood sampling, respectively.
  • Transfemoral catheterization of the left vertebral artery is then performed via the left femoral artery using a 5 french Lehman dacron catheter ( Bard, Tewksbury MA). Anaesthesia is supplemented as needed with pentobarbital (5 mg/kg, i.v.) prior to the experimental period.
  • the effects of the compounds of this invention are also examined in the chronic canine model of delayed cerebral vasospasm (two haemorrhage model of cerebral vasospasm).
  • a control vertebral angiogram is obtained and autologous blood is administered intracisternally on day 1 (as above).
  • day 3 the intracisternal administration of blood is repeated and the severe delayed vasospasm is quantitated angiographically on day 7 in all animals.
  • the effect of an infusion of test compounds on the reversal of significantly delayed cerebral vasospasm is observed.
  • 72-80 may be used to determine the anti-migraine activity of compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • SHR Three strains of mature male rats (SHR) are obtained from commercial vendors (Taconic Farms, Germantown, NY; Charles River, Danvers,
  • the femoral artery is cannulated with polyethylene tubing (PE60; Clay Adams. Parsippany, NJ) extending just into the descending aorta.
  • PE60 polyethylene tubing
  • the tubing is lead subdermally from the artery and exteriorized between the scapula just below the back of the neck and
  • MCAOO or sham surgery is carried out in the SHR, SD rats under sodium pentobarbital (65 mg/kg, i.p. and supplemented as needed) anesthesia. All animals are allowed free access to food and water prior 5 to and after surgery. Body temperature is maintained at 37°C using a heating pad throughout the surgical procedure. Surgery is conducted similar to that described previously (2.4). The right dorsal surface to the head and shaved and propped with providone-iodine, and the rat placed in a stereotaxic device (David Kopf Instruments, Tujunga, CA)
  • rats are euthanized with an overdose of sodium pentobarbital.
  • brains are removed and six coronal forebrain slices (2 mm thick) are made from the level of the olfactory bulbs to the cortical-cerebellar junction using a rat brain slicer [(59); Zivic-Miller Laboratories Inc.,
  • the swelling and infarct size are expressed in reference to the contralateral hemisphere (i.e., ipsilateral ischemic damage is normalized to the normal contralateral hemisphere). These parameters are determined for each slice to evaluate the profile of damage 30 throughout the forebrain (i.e., "fore-brain profile") and for “total” forebrain changes by using the sum of all individual slice data in these formulas.

Abstract

L'invention se rapporte à un procédé de traitement et/ou à la prophylaxie de l'anxiété, la manie, la dépression, des effets associés à l'élimination des substances toxiques telles que la cocaïne, la nicotine, l'alcool et les benzodiazépines; de troubles, tels que l'épilepsie, pouvant être traités et/ou prévenus par des agents anticonvulsifs; et au traitement ou la prévention de l'ischémie cérébrale, des troubles provenant d'hémorragie sous-arachnoïdienne, de la maladie de Parkinson, la migraine et/ou la psychose. Ce procédé consiste à administrer au malade une quantité efficace ou prophylactique d'un activateur des vannes à potassium.
EP94902046A 1992-12-11 1993-12-08 Activateurs des vannes a potassium utilises en therapie Withdrawn EP0673248A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9225860 1992-12-11
GB929225860A GB9225860D0 (en) 1992-12-11 1992-12-11 Novel treatment
PCT/GB1993/002514 WO1994013292A1 (fr) 1992-12-11 1993-12-08 Activateurs des vannes a potassium utilises en therapie

Publications (1)

Publication Number Publication Date
EP0673248A1 true EP0673248A1 (fr) 1995-09-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP94902046A Withdrawn EP0673248A1 (fr) 1992-12-11 1993-12-08 Activateurs des vannes a potassium utilises en therapie

Country Status (4)

Country Link
EP (1) EP0673248A1 (fr)
JP (1) JPH08504432A (fr)
GB (1) GB9225860D0 (fr)
WO (1) WO1994013292A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9425502D0 (en) * 1994-12-17 1995-02-15 Smithkline Beecham Plc Novel receptor
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WO1994013292A1 (fr) 1994-06-23
JPH08504432A (ja) 1996-05-14

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