EP0563036A1 - 4-azatricyclo[2.2.1.0 2,6]heptanderivate und arzneimittel - Google Patents

4-azatricyclo[2.2.1.0 2,6]heptanderivate und arzneimittel

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Publication number
EP0563036A1
EP0563036A1 EP91901866A EP91901866A EP0563036A1 EP 0563036 A1 EP0563036 A1 EP 0563036A1 EP 91901866 A EP91901866 A EP 91901866A EP 91901866 A EP91901866 A EP 91901866A EP 0563036 A1 EP0563036 A1 EP 0563036A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkyl
azatricyclo
hydrogen
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Withdrawn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
EP91901866A
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English (en)
French (fr)
Inventor
Angus M. Macleod
Richard Herbert
Karst Hoogsteen
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.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP0563036A1 publication Critical patent/EP0563036A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • 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
    • A61P25/28—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

Definitions

  • the present invention relates to a class of substituted azatricyclic compounds which stimulate central muscarinic acetylcholine receptors and therefore are useful in the treatment of neurological and mental illnesses whose clinical manifestations are due to cholinergic deficiency.
  • diseases include presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette Syndrome.
  • Alzheimer's disease the most common dementing illness, is a slowly progressive neurological disorder characterised by marked deficirs in cognitive functions including memory, attention, language and visual perception capabilities .
  • the compounds may also lower intraocular pressure and may therefore be used against glaucoma.
  • EPA- 239309 discloses a class of oxadiaozle compounds having a first substituent of low lipophilicity, and an azacyclic or azabicyclic second substituent, which are useful in the treatment of neurodegenerative disorders.
  • Published European Patent Application No. EPA-323,864 discloses a class of oxadiazoles having a first substituent selected from certain hydrocarbon groups and an azacyclic or azabicyclic substituent which also stimulate cholinergic transmission. There is no disclosure of azatricyclic structures in these specifications.
  • the compounds of the present invention are 4-azatricyclo[2.2.1.0 2,6 ]heptanes, or salts or prodrugs thereof, substituted on one of the ring carbon atoms thereof with an amide, ester, oxime ether, or an oxa- or thia-diazole or an oxa- or thia-zole ring system which may itself be substituted on its other ring carbon atoms with a substituent of low lipophilicity or a hydrocarbon substituent.
  • R 1 is -COOR 3 , -CONR 3 R 4 , -C(NR 5 )R 6 ;
  • R 3 and R 4 are each independently C 1-6 alkyl or taken together with the nitrogen to which they are attached may form a ring having up to 6 carbon atoms or
  • R 4 may also be hydrogen
  • R 5 is OA where A is C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, OCOAi where A 1 is hydrogen or A, or NHA 2 or
  • NA 3 A 4 where A 2 , A 3 and A 4 are each independently C 1-2 alkyl;
  • R 6 is hydrogen or C 1-4 alkyl provided that when R 5 is
  • R 6 is C 1-4 alkyl
  • R 1 is a heterocyclic ring system selected from
  • one of X,Y and Z represents an oxygen or sulphur atom and the remainder represent nitrogen atoms, or one of X and Y represents a nitrogen atom, the other of X and Y represents a carbon atom and Z represents an oxygen or sulphur atom, or one of X and Y represents an oxygen or sulphur atom, the other of X and Y represents a nitrogen atom and Z represents a carbon atom; and
  • R 2 represents hydrogen, halo, -CF 3 , -OR 7 ,
  • R 7 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and R 8 is hydrogen or C 1-6 alkyl.
  • alkyl groups may be straight, branched or cyclic.
  • R 1 examples include (C 1-6 alkoxy)- carbonyl such as methoxycarbonyl, -CONR 3 R 4 such as when R 3 and R 4 taken together with the nitrogen atom form a ring such as a pyrrolidine ring or a (C ⁇ _ 3 alkyl) amide or di(C 1-3 alkyl) amide such as n- or i-propylamide or N,N-diethylamide and -C(NR 5 )R 6 wherein, in R 5 , A and A 1 are selected from methyl, ethyl, allyl and propargyl, and A 2 , A 3 and A 4 are methyl.
  • R 5 examples include methoxy, ethoxy, allyloxy, propargyloxy, acetoxy and dimethylamino.
  • R 6 is preferably hydrogen or methyl, and when R 5 is -OCOA 1 or -NHA 2 , then R 6 is preferably methyl.
  • Suitable ring systems for the group R 1 include the following: 1,2,4-oxadiazole, 1,2,4- thiadiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3- oxazole, 1,3-thiazole, isoxazole and isothiazole,
  • the group R 2 is a hydrocarbon substituent, it may be C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl or aralkyl.
  • the alkyl, alkenyl or alkynyl groups may be straight, branched or cyclic groups.
  • the alkyl group comprises from 1 to 6 carbon atoms.
  • hydrocarbon group(s) may carry one or more substituents.
  • Suitable substituent groups include halo, -OR 7 , -CF 3 and
  • Particular values of the group R 2 are hydrogen, hydroxy, chloro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, amino, dimethylamino, methoxy, ethoxy, isopropoxy, n-butoxy, allyloxy and propargyloxy.
  • Preferred values are n- or iso-propyl.
  • a suitable subgroup of compounds of formula (I) are those wherein R 1 is (C 1-6 alkoxy) carbonyl such as methoxycarbonyl, -CONR 3 R 4 such as pyrrolidine carboxamide or a heterocyclic ring such as 1,2,4-oxadiazole, 1,3-oxazole or isoxazole (and their corresponding thiaanalogues); and, when R 1 is a heterocyclic ring, R 2 is hydrogen, C 1-6 alkyl such as methyl or -NR 7 R 8 such as -NH 2 .
  • One group of prodrugs of compounds of this invention have a substituent on the heterocyclic ring R 1 which is hydrolysable in vivo to an amino group.
  • Groups which are hydrolysable in vivo to an amino group on the compounds of this invention may be readily ascertained by administering the compound to a human or animal and detecting, by conventional analytical
  • the presence of the corresponding compound having an amino substituent in the urine of a human or animal examples include, for example, amido and urethane substituents, in particular a group of formula -NH.Q, wherein Q represents CHO, COR or CO 2 R, and R represents an optionally substituted hydrocarbon group.
  • the hydrocarbon group R includes groups having up to 20 carbon atoms, suitably up to 10 carbon atoms, conveniently up to 6 carbon atoms.
  • Suitable groups R include C 1-9 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl (C 1-6 ) alkyl, aryl, and aryl (C 1-6 ) alkyl.
  • the alkyl group R may be straight or branched chain and may contain, for example, up to 12 carbon atoms, suitably from 1 to 6 carbon atoms. In particular the group may be substituted methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl, n- or iso- heptyl, or n- or iso-octyl.
  • Suitable cycloalkyl groups include cyclopentyl and cyclohexyl.
  • the aryl group R includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, substitu
  • salts of the novel compounds are also included within the scope of the present invention. It will be appreciated that salts of the compounds for use in medicine will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful for the preparation of the compounds of the invention or their non-toxic salts.
  • Acid addition salts may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • salts thereof preferably non- toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
  • Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group. Such quaternary ammonium derivatives penetrate poorly into the central nervous system and are therefore useful as
  • peripherally selective muscarinic agents useful for example as antispasmodic agents, agents to reduce gastric acid secretion, agents to block the muscarinic actions of acetylcholinesterase inhibitors in the treatment of
  • the method of treatment of this invention includes a method of treating Alzheimer's disease, senile dementia of the Alzheimer type, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania or Tourette syndrome by the administration to a patient in need of such treatment of an effective amount of one or more of the novel compounds.
  • This invention therefore also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier
  • a peripherally acting cholinergic antagonist or anti-muscarinic agent.
  • the compounds of the invention may advantageously be administered together with a peripheral cholinergic
  • N-methylscopolamine such as N-methylatropine, propantheline, methantheline or glycopyrrolate.
  • the compounds of the invention can be administered orally, parenterally or rectally at a daily dose of about 0.01 to 10 mg/kg of body weight, preferably about 0.1 to 1 mg/kg, and may be administered on a regimen of 1-4 times a day.
  • a cholinergic antagonist When a cholinergic antagonist is administered, it is incorporated at its conventional dose.
  • the pharmaceutical formulations of this invention preferably are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or suppositories for oral, parenteral or rectal administration.
  • a pharmaceutical carrier e.g. conventional tabletting ingredients such as corn starch, lactose, sucrose,
  • sorbitol talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills or capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups and flavoured
  • Suitable dispersing or suspending agents for aqueous suspension include
  • methylcellulose methylcellulose, polyvinyl-pyrrolidone and gelatin.
  • the active compound When administered for the treatment of elevated intraocular pressure or glaucoma, the active compound is preferably administered topically to the eye, although systemic treatment is, as indicated, also possible.
  • the dose administered can be from as little as 0.1 to 25 mg or more per day, singly, or preferably on a 2 to 4 dose per day regimen althougn a single dose per day is
  • the active compound or an ophthalmologically acceptable salt thereof such as the hydrochloride salt is formulated into an ophthalmic preparation.
  • an ophthalmic preparation from 0.0005% to 15% by weight can be employed.
  • the objective is to administer a dose of from 0.1 to 1.0 mg per eye per day to the patient, with treatment continuing so long as the condition persists.
  • an ophthalmic solution insert, ointment or suspension for topical delivery, or a tablet, intramuscular or intravenous composition for systemic delivery, the active medicament or an equivalent amount of a salt thereof is employed, the remainder being carrier, excipients, preservatives and the like as are customarily used in such compositions.
  • the active drugs of this invention for use in treating glaucoma are suitably administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye such as a suspension, ointment, or as a solid insert.
  • a preferred composition is eye drops.
  • Formulations of these compounds may contain from 0.0005 to 15% and especially 0.05% to 2% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing or controlling elevated intraocular pressure.
  • As a unit dosage from between 0.001 to 10.0 mg, preferably 0.005 to 2.0 mg, and especially 0.1 to 1.0 mg of the compound is generically applied to the human eye, generally on a daily basis in single or divided doses so long as the condition being treated exists.
  • This invention therefore further provides a pharmaceutical formulation adapted for topical
  • composition comprising a compound of formula (I) and a carrier suitable for topical administration.
  • dosage values are believed accurate for human patients and are based on the known and presently understood pharmacology of the compounds, and the action of other similar entities in the human eye. As with all medications, dosage
  • pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as
  • emulsifying, preserving, wetting agents, bodying agents and the like as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercurie salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates,
  • gluconate buffers and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol,
  • suitable ophthalmic vehicles can be used as carrier media for the present purpose including
  • the pharmaceutical formulation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact, or a bio- erodible insert that is soluble in lacrimal fluids or otherwise disintegrates.
  • R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined
  • R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined in formula (I).
  • R 1 is -COOR 3 , -CONR 3 R 4 or a heterocyclic ring system as defined in formula (I).
  • cyclisation may be undertaken with diethylaminosulphur trifluoride by the method of A.M. MacLeod, R. Herbert and K. Hoogsteen, J. Chem. Soc. Chem. Commun.. (1990), 100.
  • the cyclisation may also be achieved using other reagents which generate a carbonium ion in the compound of formula (III) such as SOCI 2 or a strong acid eg trifluoroacetic acid.
  • the compounds of formula (I) wherein R 1 is -C(NR 5 )R 6 may be prepared by reacting a compound of formula (IV)
  • R 6 is as defined in formula (I) with a compound of formula R 5' -NH 2 (V) wherein R 5' is R 5 as defined in formula (I) or hydroxy and thereafter, if necessary, converting R 5' (when OH) to R 5 .
  • the reaction between the compounds (IV) and (V) is preferably carried out in a hydroxylic solvent such as an alcohol such as methanol or ethanol either at ambient or elevated temperature.
  • a hydroxylic solvent such as an alcohol such as methanol or ethanol either at ambient or elevated temperature.
  • R in formula (I) is OA, NHA 1 , or NA 1 A 2
  • R 5' is preferably R 5 .
  • R 5 in formula (I) is OCOA 1
  • R 5' is preferably hydroxy.
  • R 5' (when OH) to R 5 may take place by conventional acylation methods, for example by treatment with a suitable acylating agent such as an acyl halide eg. acetyl chloride.
  • a suitable acylating agent such as an acyl halide eg. acetyl chloride.
  • the compounds of formula (IV) may be prepared from the tricyclic nitrile of formula (VI):
  • the compounds of formula (IV) may be prepared from the corresponding tricyclic chlorocarbonyl compound by reaction with N,0-dimethylhydroxylamine and an alkyl lithium.
  • the nitrile (VI) may be used as an intermediate and may be converted to an ester -CO 2 R 3 or amide -CONR 3 R 4 by conventional techniques.
  • a compound of formula (VII) may be prepared by the method of C.J. Swain, CO. Kneen and R. Baker,
  • a compound of formula (III) wherein R 1 is an oxazole or thiazole may be prepared by reaction of 1-azabicyclo-[2.2.1]heptan-3-one with a metal derivative of an oxazole or thiazole of formula (VIII) wherein L represents oxygen or sulphur, R 2 is as defined in relation to formula (I) and M represents a metal atom, for example and alkali metal such as lithium.
  • the lithium derivative may be prepared, for instance, by reacting the corresponding halo-substituted such as chloro-substituted oxazole or thiazole with n-butyl lithium.
  • R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
  • R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
  • R 1 eg. oxadiazole, thiadiazole, 1,3-oxazole, 1,3-thiazole, isoxazole or isothiazole
  • an oxazole may be prepared from a carboxylic ester by reaction with the anion of an
  • Suitable reagents for generating the anion include lithium hexamethyldisilazide or lithium diisopropylamide in a solvent such as tetrahydrofuran or dimethoxyethane.
  • An isoxazole may be prepared by reacting a carboxylic ester with the anion of an oxime CH 3 C(NOH)R 2 followed by heating in an acid such as sulphuric acid.
  • the oxime anion may be formed using a strong base such as butyl lithium in a solvent such as tetrahydrofuran.
  • An oxadiazole may be prepared by reacting a carboxylic ester with an amide oxime R 2 (NOH)NH2 or a salt thereof in a solvent such as tetrahydrofuran, dimethyl formamide or a lower alkanol such as methanol, ethanol or propanol.
  • a solvent such as tetrahydrofuran, dimethyl formamide or a lower alkanol such as methanol, ethanol or propanol.
  • one substituent R 2 can be converted to another.
  • an amino group may be converted to chloro via the intermediacy of diazonium, -N 2 -
  • a chloro substituent may be converted to methoxy by reaction with a nucleophile such as methoxide
  • alkoxycarbonyl groups may be converted, via carboxy, to an amino substituent, -NH 2
  • methoxy may be converted to hydroxy by treatment with concentrated hydrobromic acid.
  • any sensitive groups in the compounds it may be necessary and/or desirable to protect any sensitive groups in the compounds.
  • the reactants employed include amino, carboxy, keto, hydroxy or thiol groups, these may be protected in conventional manner.
  • protecting groups for hydroxy groups include silyl groups such as trimethylsilyl or t-butyldimethylsilyl, and
  • etherifying groups such as tetrahydropyranyl; and for amino groups include benzyloxycarbonyl and t-butoxycarbonyl.
  • Keto groups may be protected in the form of a ketal.
  • Carboxy groups are preferably protected in a reduced form such as in the form of their corresponding protected alcohols, which may be subsequently oxidised to give the desired carboxy group.
  • Thiol groups may be protected by disulphide formation, either with the thiol itself or with another thiol to form a mixed disulphide.
  • the protecting groups may be removed at any convenient stage in the synthesis of the desired compound according to conventional techniques.
  • Each of the compounds of the Examples demonstrates an affinity for the muscarinic receptor, having an IC 50 (concentration required to displace 50% of specific [ 3 H]-N-methylscopolamine binding from rat cortical membrane preparations)
  • Acetamide oxime (140mg) was stirred in tetrahydrofuran (10ml) with NaH (55% in oil, 80mg) and type 4A molecular sieves (0.5g) for 30 minutes.
  • l-Methoxycarbonyl-4- azatricyclo[2.2.1.0 2,6 ]heptane (183mg) in tetrahydrofuran (10ml) was added and the mixture heated under reflux for 1.5 hours. The reaction was allowed to cool and filtered then evaporated under reduced pressure. The residue was partitioned between aqueous K 2 CO 3 and CH 2 Cl 2 and the organic phase separated and dried with Na 2 SO 4 . The solution was concentrated and the residue crystallised from Et 2 O/hexane to give the title compound (105mg) as white crystals, mp 75°C.
  • Acetoneoxime (210mg) was dissolved in tetrahydrofuran (5ml) and cooled to 0°C under N 2 n-Butyllithium (3.6ml) was added and the solution stirred at 0°C for 1h.
  • 1-Methoxycarbonyl-4-azatricyclo[2.2.1.0 2,6 ]heptane (350mg) in tetrahydrofuran (4ml) was then added dropwise and the reaction mixture stirred at 0°C for lh. The solution was then warmed to room temperature and stirred for a further 16h. The reaction mixture was then poured into a rapidly stirred solution of 1.2g cone. H 2 SO 4 diluted to 10ml with 4:1 tetrahydrofuran-water.
  • Compound (I) 1.0 2.0 25.0 Microcrystalline cellulose 49.25 48.75 37.25
  • Compound (I) lactose, and a portion of the corn starch are mixed together and granulated to a 10% corn starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of compound (I) per tablet.
  • the formulation is sterilised by autoclaving.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP91901866A 1990-12-21 1990-12-21 4-azatricyclo[2.2.1.0 2,6]heptanderivate und arzneimittel Withdrawn EP0563036A1 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/GB1990/002016 WO1992011261A1 (en) 1990-12-21 1990-12-21 4-azatricyclo[2.2.1.02,6]heptanes and pharmaceutical compositions

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EP0563036A1 true EP0563036A1 (de) 1993-10-06

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US5914338A (en) * 1996-04-02 1999-06-22 Novo Nordisk Heterocyclic compounds and their preparation and use
CA2340946A1 (en) 1998-08-18 2000-03-02 Anna Toy-Palmer Muscarinic agonists and antagonists
WO2012033956A1 (en) * 2010-09-08 2012-03-15 Mithridion, Inc. Cognition enhancing compounds and compositions, methods of making, and methods of treating

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CA2000041A1 (en) * 1988-10-13 1990-04-13 Barry S. Orlek Compounds
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