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Definitions

• the present invention relates to novel 1-aza-bicycloalkyl derivatives, to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
• unsubstituted or substituted means that the respective radical can by substituted by one or more, preferably up to three, especially one or two substituents.
• the substituents are preferably selected from the group consisting of amino, C 1 -C 4 alkyl amino, di(C 1 -C 4 alky)-amino, C 3 -C 5 cycloalkyl amino, di(C 3 -C 5 )cycloalkyl amino, N—C 1 -C 4 alkyl-N—C 3 -C 5 cycloalkyl amino, halogen, C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl, hydroxy, C 1 -C 4 alkoxy, C 3 -C 5 cycloalkyloxy, C 1 -C 4 alkoxy C 1 -C 4 alkoxy, di(C 1 -C 4 alkyl)-amino C 1 -C 4 alkoxy, carbamoyl, N—C
• C 5 -C 10 aryl “C 5 -C 10 heteroaryl” are to be understood as aromatic residues which are in each case unsubstituted or substituted by the substituents provided above, preferably in each case unsubstituted or substituted by one or more substituents selected from halogen, CN or alkyl, which can be unsubstituted or substituted by halogen, e.g. trifluoromethyl; or C 1 -C 4 alkoxy, or condensed, e.g. to a benzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]dioxine and/or to a further heterocyclic ring.
• C 5 -C 10 heteroaryl is an aromatic heterocyclic system wherein one or more carbon atoms are replaced by hetero atoms. Preferred are 5 to 9 membered ring systems containing one, two or three hetero atoms. Examples of C 5 -C 10 aryl or C 5 -C 10 heteroaryl residues as mentioned above include phenyl, naphthyl, isobenzofuranyl, thienyl, indolyl.
• alkyl represents a straight-chain or branched-chain alkyl group, preferably represents a straight-chain or branched-chain C 1-7 alkyl, particularly preferably represents a straight-chain or branched-chain C 1-4 alkyl; for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, with particular preference given to methyl, ethyl, n-propyl and iso-propyl.
• Alkoxy is especially C 1 -C 4 alkoxy, in particular methoxy, ethoxy or n-propoxy.
• Hetero atoms are atoms other than Carbon and Hydrogen, preferably Nitrogen (N), Oxygen (O) or Sulfur (S).
• Halogen represents Fluoro, Chloro, Bromo or Iodo, preferably represents Fluoro, Chloro or Bromo and particularly preferably represents Chloro.
• the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.
• any reference to the free compounds hereinbefore and hereinafter is to be understood as referring also to the corresponding salts, as appropriate and expedient.
• compounds of formula I are preferred, wherein the starting material of formula (III) is the ( ⁇ ) alcohol.
• Particularly preferred compounds of the invention are the compounds of the Examples.
• the present invention also provides a process for the production of a compound of formula I, which process comprises the step of reacting a compound of formula II Z—Y—R (II); wherein Y and R are as defined above for a compound of formula I and Z is a leaving group, e.g. F, Cl, Br, I or OSO 2 CF 3 , with a compound of formula III wherein A has the meaning as defined for a compound of formula I, and recovering the so obtained compound of formula I in free base or acid addition salt form.
• a leaving group e.g. F, Cl, Br, I or OSO 2 CF 3
• reaction may be carried out in accordance with standard procedures, for example as illustrated in the Examples.
• One or more functional groups may need to be protected in the starting materials by protecting groups.
• the protecting groups employed may already be present in precursors and should protect the functional groups concerned against unwanted secondary reactions, such as acylations, etherifications, esterifications, oxidations, solvolysis, and similar reactions. It is a characteristic of protecting groups that they lend themselves readily, i.e. without undesired secondary reactions, to removal, typically by solvolysis, reduction, photolysis or also by enzyme activity, for example under conditions analogous to physiological conditions, and that they are not present in the end-products.
• the specialist knows, or can easily establish, which protecting groups are suitable with the reactions mentioned hereinabove and hereinafter.
• Acid addition salts may be produced from the free bases in known manner, and vice-versa. Alternatively, optically pure starting materials can be used. Suitable acid addition salts for use in accordance with the present invention include for example the hydrochloride.
• Stereoisomeric mixtures e.g. mixtures of diastereomers
• Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This separation may take place either at the level of a starting compound or in a compound of formula I itself.
• Enantiomers may be separated through the formation of diastereomeric salts, for example by salt formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographic substrates with chiral ligands. Alternatively, optically pure starting materials can be used.
• Suitable diluents for carrying out the above-described are especially inert organic solvents. These include, in particular, aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene; petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl ether or ethylene glycol diethyl ether; ketones, such as acetone, butanone or methyl isobutyl ketone; nitriles, such as acetonitrile propionitrile or butyronitrile; amides, such as N,N-dimethylformamide, N
• Reaction temperatures can be varied within a relatively wide range.
• the processes are carried out at temperatures between 0° C. and 150° C., preferably between 10° C. and 120° C.
• Deprotonation reactions can be varied within a relatively wide range.
• the processes are carried out at temperatures between ⁇ 150° C. and +50° C., preferably between ⁇ 75° C. and 0° C.
• the compounds of the invention and their pharmaceutically acceptable acid addition salts exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.
• the compounds of the invention are found to be cholinergic ligands of the nAChR.
• preferred compounds of the invention show selective ⁇ 7-nAChR activity.
• the compounds of the present invention may in particular be found to be agonists, partial agonists, antagonists or allosteric modulators of the receptor.
• diseases or disorders related to the CNS include general anxiety disorders, cognitive disorders, learning and memory deficits and dysfunctions, Alzheimer's disease, ADHD, Parkinson's disease, Huntington's disease, ALS, prionic neurodegenerative disorders such as Creutzfeld-Jacob disease and kuru disease, Gilles de la Tourette's syndrome, psychosis, depression and depressive disorders, mania, manic depression, schizophrenia, the cognitive deficits in schizophrenia, obsessive compulsive disorders, panic disorders, eating disorders, narcolepsy, nociception, AIDS-dementia, senile dementia, mild cognitive dysfunctions related to age, autism, dyslexia, tardive dyskinesia, epilepsy, and convulsive disorders, post-traumatic stress disorders, transient anoxia, pseudodementia,
• compounds of the invention may be useful for the treatment of endocrine disorders, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias as well as angina pectoris, hyperkinesia, premature ejaculation and erectile difficulty. Still further, compounds of the invention may be useful in the treatment of inflammatory disorders (Wang et al., Nature 2003, 421, 384), disorders or conditions including inflammatory skin disorders, Crohn's diesease, inflammatory bowel disease, ulcerative colitis and diarrhoea. Compounds of the invention may further be useful for the treatment of withdrawal symptoms caused by termination of the use of addictive substances, like tobacco, nicotine, opioids, benzodiazepines and alcohol.
• addictive substances like tobacco, nicotine, opioids, benzodiazepines and alcohol.
• compounds of the invention may be useful for the treatment of pain, e.g. caused by migraine, postoperative pain, phantom limb pain or pain associated with cancer.
• the pain may comprise inflammatory or neuropathic pain, central pain, chronic headache, pain related to diabetic neuropathy, to post therapeutic neuralgia or to peripheral nerve injury.
• degenerative ocular disorders which may directly or indirectly involve the degeneration of retinal cells, including ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age-related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macular edema (CME), retinal detachment, retinitis pigmentosa, Stargardt's disease, Best's vitelliform retinal degeneration, Leber's congenital amaurosis and other hereditary retinal degenerations, pathologic myopia, retinopathy of prematurity, and Leber's hereditary optic neuropathy,
• ischemic retinopathies in general, anterior ischemic optic neuropathy, all forms of optic neuritis, age-related macular degeneration (AMD), in its dry forms (dry AMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macular e
• the compounds of the invention are used as diagnostic agents and/or PET ligands, e.g. for the identification and localization of nicotine receptors in various tissues.
• Properly isotope-labeled agents of the invention exhibit valuable properties as histopathological labeling agents, imaging agents and/or biomarkers, hereinafter “markers”, for the selective labeling of the nAChR.
• the agents of the invention are useful as markers for labeling the alpha7 nAChR receptors in vitro or in vivo.
• compounds of the invention which are properly isotopically labeled are useful as PET markers.
• Such PET markers are labeled with one or more atoms selected from the group consisting of 11 C, 13 N, 15 O, 18 F.
• the agents of the invention are therefore useful, for instance, for determining the levels of receptor occupancy of a drug acting at the nAChR, or diagnostic purposes for diseases resulting from an imbalance or dysfunction of nAChR, and for monitoring the effectiveness of pharmacotherapies of such diseases.
• the present invention provides an agent of the invention for use as a marker for neuroimaging.
• the present invention provides a composition for labeling brain and peripheral nervous system structures involving nAChR in vivo and in vitro comprising an agent of the invention.
• the present invention provides a method for labeling brain and peripheral nervous system structures involving nAChR in vitro or in vivo, which comprises contacting brain tissue with an agent of the invention.
• the method of the invention may comprise a further step aimed at determining whether the agent of the invention labeled the target structure.
• Said further step may be effected by observing the target structure using positron emission tomography (PET) or single photon emission computed tomography (SPECT), or any device allowing detection of radioactive radiations.
• PET positron emission tomography
• SPECT single photon emission computed tomography
• the agents of the invention are ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) agonists.
• the agents of the invention display high affinity at the ⁇ 7 nAChR as shown in the following tests:
• a functional assay for affinity at the ⁇ 7 nAChR is carried out with a rat pituitary cell line stably expressing the ⁇ 7 nAChR. Briefly, GH3 cells recombinantly expressing the nAChR ⁇ 7 were seeded 72 h prior to the experiment on black 96-well plates and incubated at 37° C. in a humidified atmosphere (5% CO 2 /95% air). On the day of the experiment medium was removed by flicking the plates and replaced with 100 ⁇ l growth medium containing af fluorescent calcium sensitive dye, in the presence of 2.5 mM probenicid (Sigma). The cells were incubated at 37° C.
• a similar functional assay is carried out using a human epithelial cell line stably expressing the human ⁇ 4 ⁇ 2 subtype (Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366, 235) In this assay, the preferred compounds of the invention show selectivity for the ⁇ 7 nAChR subtypes.
• the compounds of the invention induce significant sensory gating at concentrations of about 10 to about 40 ⁇ M.
• the compounds of the invention may be shown to increase attention in a test of attention for rodents (Robbins, J. Neuropsychiatry Clin. Neurosci. (2001) 13, 326-35), namely the 5-choice serial reaction time test (5-CSRTT).
• rodents Robbins, J. Neuropsychiatry Clin. Neurosci. (2001) 13, 326-35)
• 5-choice serial reaction time test 5-CSRTT
• the rat must observe a wall containing 5 holes. When a light flash appears in one of them, the rat must respond with a nose-poke into the correct hole within 5 sec. in order to receive a food pellet reward, delivered to a feeder in the opposite wall.
• Compounds of the invention may also show learning/memory enhancing effects in the social recognition test in mice and rats (Ennaceur and Delacour, Behav. Brain Res. (1988) 31, 47-59).
• the compounds of the invention are therefore useful for the prevention and treatment (including mitigation and prevention) of various disorders, especially those mentioned above.
• the usefulness of ⁇ 7 nAChR agonists in neurodegeneration is documented in the literature, e.g. in Wang et al., J. Biol. Chem. 275, 5626-5632 (2000).
• the appropriate dosage of a compound (active ingredient) of the invention will, of course, vary depending upon, for example, the host, the mode of administration and the nature and severity of the condition being treated as well as the relative potency of the particular agent of the invention employed.
• the amount of active agent required may be determined on the basis of known in vitro and in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
• satisfactory results in animals are indicated to be obtained at daily dosages of from about 0.01 to about 30.0 mg/kg p.o.
• an indicated daily dosage is in the range of from about 0.7 to about 1400 mg/day p.o., e.g.
• Oral dosage forms accordingly suitably comprise from about 1.75 or 2.0 to about 700 or 1400 mg of a compound of the invention admixed with an appropriate pharmaceutically acceptable diluent or carrier therefor.
• compositions contain, for example, from about 0.1% to about 99.9%, preferably from about 20% to about 60%, of the active ingredient(s).
• compositions comprising a compound of the invention include, for example, a solid dispersion, an aqueous solution, e.g. containing a solubilising agent, a microemulsion and a suspension of, e.g. a salt of a compound of formula I or a free compound of the formula I in the range of from 0.1 to 1%, e.g. 0.5%.
• the composition may be buffered to a pH in the range of, e.g. from 3.5 to 9.5, e.g. to pH 4.5, by a suitable buffer.
• the compounds of the invention are also commercially useful as research chemicals.
• a compound of the formula I and/or a pharmaceutically acceptable salt thereof may be administered as single active agent or in combination with one or more other active agents of the formula I and/or a pharmaceutically acceptable salt thereof or especially other active agents commonly employed especially for the treatment of the disorders mentioned herein or further other disorders, in any customary manner, e.g. orally, for example in the form of tablets, capsules, or as nasal spray, or parenterally, for example in the form of injection solutions or suspensions.
• the other active agents employed in such combinations are preferably selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), conventional antipsychotics, atypical antipsychotics, buspirone, carbamazepine, oxcarbazepine, gabapentin and pregabalin.
• SSRIs selective serotonin reuptake inhibitors
• SNRIs norepinephrine reuptake inhibitors
• conventional antipsychotics atypical antipsychotics
• buspirone carbamazepine
• oxcarbazepine gabapentin and pregabalin.
• An SSRI suitable for the present invention is especially selected from fluoxetine, fuvoxamine, sertraline, paroxetine, citalopram and escitalopram.
• An SNRI suitable for the present invention is especially selected from venlafaxine and duloxetine.
• benzodiazepines as used herein includes, but is not limited to clonazepam, diazepam and lorazepam.
• conventional antipsychotics as used herein includes, but is not limited to haloperidol, fluphenazine, thiotixene and flupentixol.
• the term “atypical antipsychotics” as used herein relates to clozaril, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazol.
• Buspirone can be administered in free form or as a salt, e.g. as its hydrochloride, e.g., in the form as marketed, e.g. under the trademark BusparTM or BesparTM. It can be prepared and administered, e.g., as described in U.S. Pat. No. 3,717,634. Fluoxetine can be administered, e.g., in the form of its hydrochloride as marketed, e.g. under the trademark ProzacTM. It can be prepared and administered, e.g., as described in CA 2002182.
• Paroxetine ((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine) can be administered, e.g., in the form as marketed, e.g. under the trademark PaxilTM. It can be prepared and administered, e.g., as described in U.S. Pat. No. 3,912,743. Sertraline can be administered, e.g., in the form as marketed, e.g. under the trademark ZoloftTM. It can be prepared and administered, e.g., as described in U.S. Pat. No. 4,536,518.
• Clonazepam can be administered, e.g., in the form as marketed, e.g. under the trademark AntelepsinTM.
• Diazepam can be administered, e.g., in the form as marketed, e.g. under the trademark Diazepam DesitinTM.
• Lorazepam can be administered, e.g., in the form as marketed, e.g. under the trademark TavorTM.
• Citalopram can be administered in free form or as a salt, e.g. as its hydrobromide, e.g., in the form as marketed, e.g. under the trademark CipramilTM.
• Escitalopram can be administered, e.g., in the form as marketed, e.g.
• CipralexTM under the trademark CipralexTM. It can be prepared and administered, e.g., as described in AU623144. Venlafaxine can be administered, e.g., in the form as marketed, e.g. under the trademark TrevilorTM. Duloxetine can be administered, e.g., in the form as marketed, e.g. under the trademark CymbaltaTM. It may be prepared and administered, e.g., as described in CA 1302421.
• Carbamazepine can be administered, e.g., in the form as marketed, e.g. under the trademark TegretalTM or TegretolTM.
• Oxcarbazepine can be administered, e.g., in the form as marketed, e.g.
• TrileptalTM Oxcarbazepine is well known from the literature [see for example Schuetz H. et al., Xenobiotica (GB), 16(8), 769-778 (1986)].
• Gabapentin can be administered, e.g., in the form as marketed, e.g. under the trademark NeurontinTM.
• Haloperidol can be administered, e.g., in the form as marketed, e.g. under the trademark Haloperidol STADATM.
• Fluphenazine can be administered, e.g., in the form of its dihydrochloride as marketed, e.g. under the trademark ProlixinTM.
• Thiothixene can be administered, e.g., in the form as marketed, e.g. under the trademark NavaneTM. It can be prepared, e.g., as described in U.S. Pat. No. 3,310,553. Flupentixol can be administered for instance in the form of its dihydrochloride, e.g., in the form as marketed, e.g. under the trademark EmergilTM or in the form of its decanoate, e.g., in the form as marketed, e.g. under the trademark DepixolTM. It can be prepared, e.g., as described in BP 925,538.
• Clozaril can be administered, e.g., in the form as marketed, e.g. under the trademark LeponexTM. It can be prepared, e.g., as described in U.S. Pat. No. 3,539,573.
• Risperidone can be administered, e.g., in the form as marketed, e.g. under the trademark RisperdalTM.
• Olanzapine can be administered, e.g., in the form as marketed, e.g. under the trademark ZyprexaTM.
• Quetiapine can be administered, e.g., in the form as marketed, e.g. under the trademark SeroquelTM.
• Ziprasidone can be administered, e.g., in the form as marketed, e.g. under the trademark GeodonTM. It can be prepared, e.g., as described in GB 281,309. Aripiprazole can be administered, e.g., in the form as marketed, e.g. under the trademark AbilifyTM. It can be prepared, e.g., as described in U.S. Pat. No. 5,006,528.
• the pharmaceutical compositions for separate administration of the combination partners and/or those for administration in a fixed combination i.e. a single galenical composition comprising at least two combination partners
• a single galenical composition comprising at least two combination partners can be prepared in a manner known per se and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals, including man, comprising a therapeutically effective amount of at least one pharmacologically active combination partner alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application.
• compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or furthermore ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount can instead with a single dosage unit also be reached by administration of a two or more dosage units.
• a therapeutically effective amount of each of the combination partners may be administered simultaneously or sequentially and in any order, and the components may be administered separately (e.g. sequentially after fixed or variable periods of time), or as a fixed combination.
• the method of treatment (including mitigation) of a disorder according to the invention may comprise (i) administration of the combination partner (a) (a compound of the present invention) in free or pharmaceutically acceptable salt form and (ii) administration of a combination partner (b) (e.g. a different compound of the present invention or an active ingredient of a different formula) in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g.
• administering also encompasses the use of a pro-drug of a combination partner that convert in vivo to the combination partner as such.
• the instant invention is therefore to be understood as embracing all such regimes of simultaneous and/or alternating treatment and the term “administering” is to be interpreted accordingly.
• the effective dosage of the combination partners employed may vary, for example depending on the particular compound or pharmaceutical composition employed, the mode of administration, the disorder being treated, and/or the severity of the disorder being treated.
• the dosage regimen is selected in accordance with a variety of factors including the route of administration, metabolism by and the renal and hepatic function of the patient.
• a physician, clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the single active ingredients required to prevent, mitigate, counter or arrest the disorder.
• Optimal precision in achieving concentration of the active ingredients within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the active ingredients' availability to target sites.
• the present invention also provides:
• a pharmaceutical composition comprising a compound of the formula I, and/or a pharmaceutically acceptable salt thereof, as active ingredient together with a pharmaceutically acceptable diluent or carrier.
• a method for the treatment of a disorder comprising administering a pharmaceutically effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
• a method for treating or preventing a disorder in the treatment of which alpha-7 receptor activation plays a role or is involved and/or in which alpha-7 receptor activity is involved comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the formula I, and/or a pharmaceutically acceptable salt thereof.
• a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of an alpha-7 agonist of the formula I, and/or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active compound and/or a pharmaceutically acceptable salt thereof, said second pharmaceutically active compound and/or salt thereof being especially for use in the treatment of any one or more of the disorders set forth hereinbefore or hereinafter.
• a combination comprising a therapeutically effective amount of an alpha-7 agonist of the formula I, and/or a pharmaceutically acceptable salt thereof, and a second pharmaceutically active compound and/or a pharmaceutically acceptable salt thereof, said second pharmaceutically active compound being especially for use or of use in the treatment of any one or more of the particular disorders set forth hereinbefore.
• Potassium trimethylsilylamine (5.25 mmol) is added to a solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (5.0 mmol) in THF (20 ml) at room temperature and the solution is stirred for 30 min.
• the resulting potassium alcoholate is slowly added to a precooled solution of 3,6-dichloropyridazine (7.5 mmol) in THF (50 ml) and the resulting mixture is stirred for another 20 minutes.
• the solution is allowed to warm to 0° C. is quenched with brine and extracted with diethylether.
• the organic layer is dried over magnesium sulfate and evaporated.
• the brown oil is purified by silica gel column chromatography (CH 2 Cl 2 :MeOH:NH 3 , 9:1:0.1) to afford (rac.)-4-(6-Chloro-pyridazin-3-yloxy)-1-aza-bicyclo[3.3.1]nonane (320 mg).
• Preparation process The pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefossé S. A., Saint Priest, France) and ground in a wet pulverizer to produce a particle size of about 1 to 3 ⁇ m. 0.419 g portions of the mixture are then introduced into soft gelatin capsules using a capsule-filling machine.
• Lauroglykol® propylene glycol laurate, Gattefossé S. A., Saint Priest, France

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