WO1995022327A1 - Utilisation des imidazoles 1-(arylalkylaminoalkyle) dans le traitement des lesions neurologiques - Google Patents

Utilisation des imidazoles 1-(arylalkylaminoalkyle) dans le traitement des lesions neurologiques Download PDF

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Publication number
WO1995022327A1
WO1995022327A1 PCT/EP1995/000625 EP9500625W WO9522327A1 WO 1995022327 A1 WO1995022327 A1 WO 1995022327A1 EP 9500625 W EP9500625 W EP 9500625W WO 9522327 A1 WO9522327 A1 WO 9522327A1
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WIPO (PCT)
Prior art keywords
group
alkyl group
halo
propylamine
phenyl
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PCT/EP1995/000625
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English (en)
Inventor
John Gareth Bowen
Patricia Lesley Needham
Leslie Steele
Original Assignee
Knoll Ag
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Filing date
Publication date
Priority claimed from GB9403306A external-priority patent/GB9403306D0/en
Priority claimed from GBGB9425773.0A external-priority patent/GB9425773D0/en
Application filed by Knoll Ag filed Critical Knoll Ag
Priority to AU18912/95A priority Critical patent/AU1891295A/en
Publication of WO1995022327A1 publication Critical patent/WO1995022327A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines

Definitions

  • This invention relates to 1-(arylalkylaminoalkyl) imidazole compounds which are useful in the treatment of neurological damage.
  • US 5,192,753 describes a method of treating dementia which comprises the administration of a sufficient amount of a non-steroidal anti-inflammatory drug to inhibit prostaglandin synthesis in vivo but insufficient to induce unwanted side-effects in said human.
  • the non-steroidal anti-inflammatory drugs disclosed are characterised by their ability to inhibit prostaglandin synthesis through anti-cyclooxygenase activity and are hereinafter referred to as traditional non-steroidal anti-inflammatory drugs.
  • WO 93/13075 discloses certain 1-(arylalkyl-aminoalkyl) imidazole derivatives which have a novel profile of anti-inflammatory activity. These compounds are not traditional non-steroidal anti-inflammatory drugs in that they do not inhibit cyclooxygenase, nor are they pro-drugs for inhibitors of cyclooxygenase. Consequently these compounds are not expected to display the unwanted side-effects associated with traditional non-steroidal anti-inflammatory drugs. Traditional non-steroidal anti-inflammatory drugs do not penetrate the brain to any appreciable extent.
  • indomethacin is almost completely protein bound in plasma and consequently, since the protein bound indomethacin cannot cross the blood-brain barrier, only a minute proportion of the administered dose penetrates the brain.
  • WO 93/13075 which had been radiolabelled, a significant amount of the radiolabel was rapidly detected in the brain. The present invention has been developed from this observation.
  • the present invention provides a method of treating neurological damage, in which a therapeutically or prophylactically effective amount of a compound of formula I
  • R 1 , R 2 and R 3 independently represent hydrogen, halo, a C 1-6 alkyl group, a C 1-6 alkoxy group, phenoxy (optionally substituted by a C 1-4 alkyl group, a C 1-4 alkoxy group or halo), phenyl (optionally substituted by a C 1-4 alkyl group, a C 1-4 alkoxy group or halo), a C 2-6 alkoxycarbonyl group, an amino group of formula -NR 13 R 14 (in which R 13 and R 14 are independently hydrogen or a C 1-4 alkyl group or R 13 and R 14 together with the nitrogen atom to which they are attached represent a pyrrolidine ring, a morpholine ring or a piperidine ring), a halogenated C 1-4 alkoxy group, a halogenated C 1-4 alkyl group, benzyloxy (optionally substituted by a C 1-4 alkyl group, a C 1-4 alkoxy group or hal
  • R 4 and R 5 independently represent hydrogen, a C 1-4 alkyl group, phenyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group) or R 4 and R 5 together with the carbon atom to which they are attached represent a C 3-6 cycloalkyl group;
  • R 6 represents hydrogen, a C 1-4 alkyl group or an ⁇ -hydroxy C 1-4 alkyl group
  • A represents a C 2-9 alkylene group, which may be straight or branched;
  • R 8 represents hydrogen, a C 1-6 alkyl group, halo, a C 1-4 alkoxy group, a C 1-4 hydroxyalkyl group, phenyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group) or benzyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group);
  • R 9 and R 10 independently represent hydrogen, a C 1-6 alkyl group, halo, a C 1-4 alkoxy group, phenyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group), a C 1-4 hydroxyalkyl group, a C 2-6 alkoxycarbonyl group, nitro, an amino group of formula NR 30 R 31 (in which R 30 and R 31 independently represent hydrogen or a
  • a group containing a chain of 3 or more carbon atoms may be straight or branched, for example propyl includes n-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyl and tert-butyl.
  • the compounds of formula I are advantageous in the treatment of neurological damage as they are expected to have improved efficacy and reduced side-effects compared to the proposed therapies referred to in US 5,192,753 above.
  • the compounds of formula I are expected to show reduced irritation in the gastrointestinal tract after oral administration.
  • neurodegenerative diseases including inter alia Dementia, Alzheimer's Disease, Parkinson's Disease, Huntington's Chorea, Pick's Disease, Post Traumatic Dementia and Creutzfeldt-Jakob's Disease.
  • the compounds of formula I are useful in the treatment of dementia, and in particular Alzheimer's disease.
  • the present invention provides a method of treating dementia, and in particular Alzheimer's disease, in which a therapeutically or prophylactically effective amount of a compound of formula I is administered in conjunction with a pharmaceutically acceptable diluent or carrier, to a mammal in need thereof.
  • R 1 , R 2 and R 3 independently represent hydrogen, halo (for example bromo, chloro or fluoro), a C 1-4 alkyl group (for example methyl, ethyl, propyl or butyl), a C 1-4 alkoxy group (for example methoxy, ethoxy, propoxy or butoxy), phenoxy, phenyl, a C 2-6 alkoxycarbonyl group
  • R 13 and R 14 are independently hydrogen or a C 1-2 alkyl group (for example amino, methylamino, dimethylamino, ethylamino or diethylamino), a polyhalo C 1-2 alkoxy group (for example trifluoromethoxy or pentafluoroethoxy), a polyhalo C 1-2 alkyl group (for example trifluoromethyl or pentafluoroethyl), benzyloxy, hydroxy, a (C 2-6 alkoxycarbonyl)vinyl group; a C 2-6 alkoxycarbonyl C 1-2 alkyl group, or R 1 and R 2 together with the phenyl ring to which they are attached represent a naphthyl group; R 4 and R 5 independently represent hydrogen, a C 1-4 alkyl group (for example amino, methylamino, dimethylamino, ethylamino or diethylamino), a polyhalo C 1-2 alkoxy group (for
  • R 6 represents hydrogen or a C 1-4 alkyl group (for example methyl, ethyl, propyl or butyl);
  • A represents a C 2-7 alkylene group which may be straight or branched, (for example ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene, 2,2-dimethylethylene or heptamethylene);
  • R 8 represents hydrogen, a C 1-4 alkyl group (for example methyl, ethyl, propyl or butyl), phenyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group) or benzyl (optionally substituted by a C 1-4 alkyl group, halo or a C 1-4 alkoxy group); and R 9 and R 10 independently represent hydrogen, a C 1-4 alkyl group (for example methyl, ethyl, propyl or butyl), halo (for example bromo, chloro or fluoro), a C 1-4 hydroxyalkyl group (for example hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl), a C 2-6 alkoxycarbonyl group (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl), nitro or a C 1-6 alkanoyloxy C 1-2 alkyl group (
  • R 1 represents halo, a C 1-4 alkyl group, a C 2-4 alkoxy group, phenoxy, phenyl, a C 2-4 alkoxycarbonyl group, a perhalo C 1-2 alkoxy group, a perhalo C 1-2 alkyl group, benzyloxy, an amino group of formula NR 13 R 14 (in which R 13 and R 14 independently represent hydrogen or a C 1-4 alkyl group), a (C 2-4 alkoxycarbonyl)vinyl group, a C 2-6 alkoxycarbonyl C 1-2 alkyl group, or R 1 and R 2 together with the phenyl ring to which they are attached represent a naphthyl group;
  • R 2 and R 3 independently represent hydrogen, halo, a C 1-4 alkyl group, a C 1-4 alkoxy group, a perhalo C 1-2 alkyl group, or hydroxy;
  • R 4 and R 5 independently represent hydrogen, a C 1-4 alkyl group, phenyl or R 4 and R 5 together with the carbon atom to which they are attached represent a C 3-6 cycloalkyl group;
  • R 6 represents hydrogen or a C 1-3 alkyl group;
  • A represents ethylene, trimethylene, tetramethylene, 1,1-dimethylethylene or heptamethylene
  • R 8 represents hydrogen, a C 1-4 alkyl group, phenyl or benzyl; and R 9 and R 10 independently represent hydrogen, a C 1-4 alkyl group, halo, a C 1-4 hydroxyalkyl group, a C 2-6 alkoxycarbonyl group, nitro, or a C 1-6 alkanoyloxy C 1-2 alkyl group.
  • R 1 represents bromo, chloro, methyl, ethyl, t-butyl, butoxy, phenoxy, phenyl, me thoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, dimethylamino, trifluoromethoxy, trifluoromethyl, benzyloxy, 2-ethoxycarbonylvinyl or R 1 and R 2 together with the phenyl ring to which they are attached represent a naphthyl group.
  • R 1 represents bromo, chloro, t-butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, propoxycarbonyl, trifluoromethoxy, trifluoromethyl, benzyloxy, 2-ethoxycarbonylvinyl or R 1 and R 2 together with the phenyl ring to which they are attached represent a naphthyl group. Most preferably R 1 represents bromo or chloro.
  • R 2 represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2-methyl, 3-methyl, 2-methoxy, 2-ethoxy, 2-hydroxy or 3- trifluoromethyl and R 3 represents hydrogen, 2-chloro or 3-chloro. More preferably R 2 represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2 -methyl, 3-methyl, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R 3 represents hydrogen. Most preferably R 2 represents hydrogen or 2-chloro and R 3 represents hydrogen.
  • R 4 and R 5 independently represent hydrogen, methyl, ethyl or R 4 and R 5 together with the carbon atom to which they are attached represent a cyclopropyl group. More preferably R 4 and R 5 both represent hydrogen or methyl. Most preferably R 4 and R 5 both represent methyl.
  • R 6 represents hydrogen or methyl. More preferably R 6 represents hydrogen.
  • A represents ethylene, trimethylene or tetramethylene. More preferably A represents ethylene or trimethylene.
  • R 8 represents hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl. More preferably R 8 represents hydrogen or methyl.
  • R 9 and R 10 independently represent hydrogen, methyl, chloro, hydroxymethyl, ethoxycarbonyl, nitro or acetoxymethyl. More preferably R 9 and R 10 independently represent hydrogen, methyl, chloro, acetoxymethyl or ethoxycarbonyl. Most preferably R 9 and R 10 independently represent hydrogen or methyl.
  • a second group of more preferred compounds of formula I is represented by formula II in which R 1 , R 2 and R 3 represent hydrogen, R 4 and R 5 represent ethyl, R 6 represents hydrogen, A represents ethylene, R 8 represents hydrogen or C 1-4 alkyl and R 9 and R 10 independently represent hydrogen, methyl, hydroxymethyl or acetoxymethyl.
  • a third group of more preferred compounds of formula I is represented by formula II in which R 1 represents chloro; R 2 represents hydrogen or 3-chloro; R 3 represents hydrogen; R 4 , R 5 , and R 6 each represent hydrogen; A represents ethylene; R 8 represents hydrogen or methyl and R 9 and R 10 independently represent hydrogen or methyl.
  • Specific compounds of formula I are:
  • An especially preferred compound is N-[1-(4-chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)-propylamine.
  • the compounds of formula I may form organic or inorganic salts, for example, the compounds of formula I may form acid addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulphuric acid, hydriodic acid, phosphoric acid, maleic acid, acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecanoic acid and acidic amino acids such as glutamic acid.
  • Some compounds of formula I may form base addition salts, for example, with alkali metals for example sodium hydroxide, or with aminoacids for example, lysine or arginine.
  • salts may be used in therapy in place of the corresponding compounds of formula I.
  • Such salts are prepared by reacting the compound of formula I with a suitable acid or base in a conventional manner.
  • Such salts may also exist in form of solvates (for example, hydrates).
  • a compound of formula I When a compound of formula I contains a single chiral centre it may exist in two enantiomeric forms.
  • the present invention includes individual enantiomers and mixtures of those enantiomers.
  • the enantiomers may be obtained by methods known to those skilled in the art.
  • Such methods typically include resolution via formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallisation, gas-liquid or liquid chromatography; selective reaction of one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound of formula I When a compound of formula I contains more than one chiral centre it may exist in diastereoisomeric forms.
  • the diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example, chromatography or crystallisation and the individual enantiomers within each pair may be separated as described above.
  • the present invention includes each diastereoisomer of compounds of formula I or II and mixtures thereof.
  • Certain compounds of formula I may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof.
  • Certain compounds of formula I may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.
  • the term "active compound” denotes a 1-(arylalkylaminoalkyl) imidazole derivative of formula I.
  • the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a systemic effect.
  • the active compounds may be administered in a prophylactic manner.
  • the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for such methods of administration.
  • the compositions may be formulated in a manner known to those skilled in the art so as to give a controlled release, for example rapid release or sustained release, of the compounds of the present invention.
  • Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy.
  • the compositions of the invention suitably contain 0.1-90% by weight of active compound.
  • the compositions of the invention are generally prepared in unit dosage form.
  • compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.
  • the excipients used in the preparation of these compositions are the excipients known in the pharmacists' art.
  • Tablets may be prepared from a mixture of the active compound with fillers, for example, lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods.
  • the tablets may, if desired, be coated using known methods and excipients which may include enteric coating using for example hydroxypropylmethyl-cellulose phthalate.
  • the tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention.
  • Such tablets may if desired be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
  • capsules for example hard or soft gelatin capsules containing the active compound with or without added excipients, may be prepared by known methods and, if desired, provided with enteric coatings in a known manner.
  • the contents of the capsule may be formulated using known methods to give sustained release of the active compound.
  • Enteric coated compositions of the invention may be advantageous, depending on the nature of the active compound.
  • the tablets and capsules may conveniently each contain 1-1000 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg) of the active compound.
  • compositions for oral administration include, for example, aqueous suspensions containing the compound of formula I in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sunflower oil.
  • a non-toxic suspending agent such as sodium carboxymethylcellulose
  • oily suspensions containing a compound of the present invention in a suitable vegetable oil for example sunflower oil.
  • the active compound may be formulated into granules with or without additional excipients.
  • the granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion.
  • the granules may contain disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
  • compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such adminstration, for example suppositories with hard fat, semi-synthetic glycerides or polyethylene glycol bases.
  • compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.
  • compositions for topical administration may comprise a matrix in which the active compound is dispersed so that it is held in contact with the skin in order to administer the compound of formula I transdermally.
  • the active compound may be dispersed in a cream, gel or ointment base or applied in the form of a spray.
  • compositions of the invention suitable for inhalation via the mouth and/or the nose are the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders.
  • Metered dose systems known to those skilled in the art, may be used.
  • compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.
  • the compounds of the present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion or from a source of the compound placed within the body.
  • Internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example a synthetic resin or waxy material for the compound to be infused.
  • the support may be a single body containing all the compound or a series of several bodies each containing part of the compound to be delivered.
  • the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
  • the pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat neurological damage in human beings. In such treatment the amount of the compound of formula I administered per day is in the range 0.1 to 3000 mg.
  • Specific compounds which may be incorporated into the compositions of this invention are the compounds disclosed above.
  • the therapeutic activity of the compounds according to the present invention may be demonstrated by tests on standard laboratory animals. These include techniques such as transvascular occlusion of the middle cerebral artery in rats and the rat bilateral carotid occlusion global model.
  • the therapeutic activity of the compounds according to the present invention may also be demonstrated by their ability to inhibit superoxide production in purified mouse microglial cells which have been exposed to aluminosilicate as described by Evans et al in Free Radicals and Aging, pages 178-189, edited by I. Emerit & B. Chance, published by Birkhauser Verlag, 1992, and references cited therein.
  • Electroconvulsive shock treatment (ECST) to rats has been shown to inhibit the acquisition and retention of memory in a passive avoidance model (Leher, B. et al, 1986, Physiology & Behaviour, 36; 471-475).
  • the therapeutic activity of the compounds of the present invention may be determined, using this model, by their efficacy to prevent this inhibition.
  • anaesthetised rats receive ECST sufficient to cause a tonic-clonic seizure (or sham-seizure where electrodes are attached, but no current passed), on five occasions over ten days.
  • Passive avoidance training and testing are conducted in a two-chamber shuttle-box, with one chamber brightly lit, and the other dark.
  • animals In acquisition tests, animals are allowed to explore the light chamber, prior to a door to a dark chamber being opened. The time taken to enter the dark chamber is measured. Upon entry the rats receive an aversive, inescapable footshock.
  • a suitable dose for enteral administration to mammals is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses.
  • a suitable dose is generally within the range 0.01-80 mg/kg/day, more usually 0.2-40 mg/kg/day given in single or divided doses or by continuous infusion.
  • Oral administration is preferred.
  • the present invention provides the use of a compound of formula I in the manufacture of a medicament for use in the therapeutic or prophylactic treatment of neurological damage.
  • the present invention provides the use of a compound of formula I in the manufacture of a medicament for use in the treatment of dementia and in particular Alzheimer's disease.
  • the compounds of the present invention may be prepared as described in WO 93/13075.
  • Example V Tablets are prepared from the following ingredients.
  • Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with magnesium stearate and he rest of the starch. The mixture is then compressed in a tableting machine to give tablets containing 10 mg of active compound.
  • Tablets are prepared by the method of the previous Example.
  • the tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1).
  • Example X In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of semi-synthetic glycerides as the suppository base and the mixture formed into suppositories each containing 100 mg of active ingredient.
  • Example Z In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 50 mg of active ingredient.
  • Example Z In the preparation of capsules, 50 parts by weight of active compound, 300 parts by weight of lactose and 3 parts by weight of magnesium stearate are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing 50 mg of active ingredient.
  • Example Z Example Z
  • the active compound is incorporated into the base by thorough homogenization until the drug is evenly distributed.
  • the ointment is packed into 10 g amber jars with screw-capped lined lids.

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Abstract

Procédé de traitement des lésions neurologiques dans lequel on utilise une dose thérapeutique ou prophylactique efficace d'un composé de la formule (I) et des sels pharmaceutiquement acceptables de celui-ci. Dans cette formule, R1, R2 et R3 représentent indépendamment hydrogène, halo, alkyle, alcoxy, phénoxy, phényle, alcoxycarbonyle, -NR13R14, alcoxy halogéné, alkyle halogéné, benzyloxy, hydroxy, hydroxyalkyle, (alcoxycarbonyle C2-6)-vinyle, -S(O)nR7, carbamoylalkyle, alcoxycarbonylalkyle, -CONR11R12, ou bien R1 et R2 représentent, avec le noyau phényle, un groupe naphtyle; R4 et R5 représentent indépendamment hydrogène, alkyle, phényle ou ils représentent, avec l'atome de carbone, cycloalkyle C3-6; R6 représente hydrogène, alkyle, ou φ-hydroxy alkyle; A représente alkylène C2-9; R8 représente hydrogène, alkyle, halo, alcoxy, hydroxyalkyle, benzyle ou phényle; R9 et R10 représentent indépendamment hydrogène, alkyle, halo, alcoxy, phényle, hydroxyalkyle, alcoxycarbonyle, nitro, -NR30R31, alcanoyloxyalkyle, ou aminométhyle. On administre ce composé conjointement avec un diluant ou excipient pharmaceutiquement acceptable à un mammifère nécessitant cette médication. On peut utiliser ces composés pour traiter les traumatismes crâniens, l'ischémie cérébrale, les hémorragies, les blessures crâniennes, les ictus ainsi que les maladies neurodégénératives, notamment entre autres, la démence, la maladie d'Alzheimer, la maladie de Parkinson, la chorée de Huntington, la maladie de Pick, la démence post-traumatique ainsi que la maladie de Creutzfeldt-Jakob.
PCT/EP1995/000625 1994-02-22 1995-02-16 Utilisation des imidazoles 1-(arylalkylaminoalkyle) dans le traitement des lesions neurologiques WO1995022327A1 (fr)

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AU18912/95A AU1891295A (en) 1994-02-22 1995-02-16 Use of 1-(arylalkylaminoalkyl) imidazoles for treating neurological damage

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GB9403306A GB9403306D0 (en) 1994-02-22 1994-02-22 Medical treatment
GB9403306.5 1994-02-22
GB9425773.0 1994-12-20
GBGB9425773.0A GB9425773D0 (en) 1994-12-20 1994-12-20 Medical treatment

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Cited By (11)

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WO1997040035A1 (fr) * 1996-04-19 1997-10-30 Neurosearch A/S 1-(4-piperidyl)-benzimidazoles presentant une activite neurotrophique
WO2004098591A3 (fr) * 2003-05-05 2005-03-31 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
JP2006525278A (ja) * 2003-05-05 2006-11-09 プロビオドルグ エージー グルタミニル、及びグルタミン酸シクラーゼのエフェクターの使用
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7304086B2 (en) 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7335645B2 (en) 1999-08-24 2008-02-26 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US7560473B2 (en) 2001-01-19 2009-07-14 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
US7667044B2 (en) 2003-11-03 2010-02-23 Probiodrug Ag Compounds for the treatment of neurological disorders

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WO1993013075A1 (fr) * 1991-12-23 1993-07-08 The Boots Company Plc Derives d'imidazole-1-(arylalcoyle-aminoalcoyle), procedes de preparation et utilisation comme agents therapeutiques

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EP0117462A2 (fr) * 1983-02-28 1984-09-05 American Cyanamid Company N-(2-4-(1H-imidazol-1-yl)alkyl)arylamides
US5192753A (en) * 1991-04-23 1993-03-09 Mcgeer Patrick L Anti-rheumatoid arthritic drugs in the treatment of dementia
WO1993013075A1 (fr) * 1991-12-23 1993-07-08 The Boots Company Plc Derives d'imidazole-1-(arylalcoyle-aminoalcoyle), procedes de preparation et utilisation comme agents therapeutiques

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6180649B1 (en) 1996-04-19 2001-01-30 Nerosearch A/S 1-(4-piperidyl)-benzimidazoles having neurotrophic activity
WO1997040035A1 (fr) * 1996-04-19 1997-10-30 Neurosearch A/S 1-(4-piperidyl)-benzimidazoles presentant une activite neurotrophique
US7335645B2 (en) 1999-08-24 2008-02-26 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7560473B2 (en) 2001-01-19 2009-07-14 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences, P.L.A. Amine derivative with potassium channel regulatory function, its preparation and use
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7368576B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
JP2006525278A (ja) * 2003-05-05 2006-11-09 プロビオドルグ エージー グルタミニル、及びグルタミン酸シクラーゼのエフェクターの使用
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
WO2004098591A3 (fr) * 2003-05-05 2005-03-31 Probiodrug Ag Inhibiteurs de glutaminyl-cyclase
US7655684B2 (en) 2003-05-05 2010-02-02 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US7667044B2 (en) 2003-11-03 2010-02-23 Probiodrug Ag Compounds for the treatment of neurological disorders
US7304086B2 (en) 2004-02-05 2007-12-04 Probiodrug Ag Inhibitors of glutaminyl cyclase

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AU1891295A (en) 1995-09-04

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