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WO1996036637A1 - Compositions pharmaceutiques destinees a la prophylaxie et au traitement des troubles du systeme nerveux central - Google Patents

Compositions pharmaceutiques destinees a la prophylaxie et au traitement des troubles du systeme nerveux central Download PDF

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Publication number
WO1996036637A1
WO1996036637A1 PCT/US1996/004536 US9604536W WO9636637A1 WO 1996036637 A1 WO1996036637 A1 WO 1996036637A1 US 9604536 W US9604536 W US 9604536W WO 9636637 A1 WO9636637 A1 WO 9636637A1
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WO
WIPO (PCT)
Prior art keywords
compound
azabicyclo
ene
pyridyl
hept
Prior art date
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PCT/US1996/004536
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English (en)
Inventor
Merouane Bencherif
William Scott Caldwell
Gary Maurice Dull
Patrick Michael Lippiello
Peter Anthony Crooks
Balwinder Singh Bhatti
Niranjan Madhukar Deo
Alain Ravard
Original Assignee
R.J. Reynolds Tobacco Company
University Of Kentucky Research Foundation
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.)
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Publication date
Priority claimed from US08/437,153 external-priority patent/US5583140A/en
Application filed by R.J. Reynolds Tobacco Company, University Of Kentucky Research Foundation filed Critical R.J. Reynolds Tobacco Company
Priority to AU53831/96A priority Critical patent/AU5383196A/en
Publication of WO1996036637A1 publication Critical patent/WO1996036637A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems

Definitions

  • the present invention relates to compounds having pharmaceutical properties, and in particular, to compounds useful for preventing and treating central nervous system (CNS) disorders.
  • the present invention relates to a method for treating patients suffering from or susceptible to such disorders, and in particular, to a method for treating patients suffering from those disorders which are associated with neurotransmitter system dysfunction.
  • the present invention also relates to compositions of matter useful as pharmaceutical compositions in the prevention and treatment of CNS disorders which have been attributed to neurotransmitter system dysfunction.
  • CNS disorders are a type of neurological disorder.
  • CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
  • CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
  • CNS disorders There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
  • CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency.
  • CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
  • Senile dementia of the Alzheimer's type is a debilitating neurodegenerative disease, mainly afflicting the elderly; characterized by a progressive intellectual and personality decline, as well as a loss of memory, perception, reasoning, orientation and judgment.
  • One feature of the disease is an observed decline in the function of cholinergic systems, and specifically, a severe depletion of cholinergic neurons (i.e., neurons that release acetylcholine, which is believed to be a neurotransmitter involved in learning and memory mechanisms). See, Jones, et al., Intern. J. Neurosci., Vol. 50, p. 147 (1990); Perry, Br. Med. Bull., Vol. 42, p.
  • Parkinson's disease is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity. A feature of the disease appears to involve the degeneration of dopaminergic neurons (i.e., which secrete dopamine).
  • dopaminergic neurons i.e., which secrete dopamine.
  • One symptom of the disease has been observed to be a concomitant loss of nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion.
  • nicotinic receptors which are associated with such dopaminergic neurons, and which are believed to modulate the process of dopamine secretion.
  • PD PD-specific neurodegenerative diseases
  • Sinemet CR which is a sustained-release tablet containing a mixture of carbidopa and levodopa, available from The DuPont Merck Pharmaceutical Co.
  • Eldepryl which is a tablet containing selefiline hydrochloride, available from Somerset Pharmaceuticals, Inc.
  • Parlodel which is a tablet containing bromocriptine mesylate, available from Sandoz Pharmaceuticals Corporation.
  • Another method for treating PD and a variety of other neurodegenerative diseases has been proposed in U.S. Patent No. 5,210,076 to Principle et al.
  • Tourette's syndrome is an autosomal dominant neuropsychiatric disorder characterized by a range of neurological and behavioral symptoms. Typical symptoms include (i) the onset of the disorder before the age of 21 years, (ii) multiple motor and phonic tics although not necessarily concurrently, (iii) variance in the clinical phenomenology of the tics, and (iv) occurrence of quasi daily tics throughout a period of time exceeding a year.
  • Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing; while phonic or vocal tics include throat clearing, sniffling, yelping, tongue clicking and uttering words out of context.
  • Haldol which is haloperidol available from McNeil Pharmaceutical
  • Catapres which is clonidine available from Boehringer Ingelheim Pharmaceuticals, Inc.
  • Orap which is pimozide available from Gate Pharmaceuticals
  • Prolixin which is fluphenazine available from Apothecon Division of Bristol-Myers Squibb Co.
  • Klonopin which is clonazepam available from Hoffmann-LaRoche Inc.
  • Attention deficit disorder is a disorder which affects mainly children, although ADD can affect adolescents and adults. See, Vinson, Arch. Fam. Med.. Vol. 3(5), pp. 445-451 (1994); Hechtman. J. Psychiatry Neurosci.. Vol. 19 (3), pp. 193-201 (1994); Faraone et al., Biol. Psychiatry, Vol. 35(6), pp. 398-402 (1994) and Malone et al.. J. Child Neurol.. Vol. 9(2), pp. 181-189 (1994). Subjects suffering from the disorder typically have difficulty concentrating, listening, learning and completing tasks; and are restless, fidgety, impulsive and easily distracted.
  • Attention deficit disorder with hyperactivity includes the symptoms of ADD as well as a high level of activity (e.g., restlessness and movement).
  • Attempts to treat ADD have involved administration of Dexedrine, which is a sustained release capsule containing dextroamphetamine sulfate, available from SmithKline Beecham Pharmaceuticals; Ritalin, which is a tablet containing methylphenidate hydrochloride, available from Ciba Pharmaceutical Company; and Cylert, which is a tablet containing premoline, available from Abbott Laboratories.
  • Dexedrine which is a sustained release capsule containing dextroamphetamine sulfate, available from SmithKline Beecham Pharmaceuticals
  • Ritalin which is a tablet containing methylphenidate hydrochloride, available from Ciba Pharmaceutical Company
  • Cylert which is a tablet containing premoline, available from Abbott Laboratories.
  • administration of nicotine to an individual improves that individual's selective and sustained attention. See, Warburton et
  • Schizophrenia is characterized by psychotic symptoms including delusions, catatonic behavior and prominent hallucinations, and ultimately results in a profound decline in the psychosocial affect of the subject suffering therefrom.
  • schizophrenia has been treated with Klonopin, which is available as a tablet containing clonezepam, available from Hoffmann-LaRoche Inc.; Thorazine, which is available as a tablet containing chlorpromazine, available from SmithKline Beecham Pharmaceuticals; and Clozaril, which is a tablet containing clozapine, available from Sandoz Pharmaceuticals.
  • Such neuroleptics are believed to be effective as a result of interaction thereof with the dopaminergic pathways of the CNS.
  • Nicotine has been proposed to have a number of pharmacological effects. Certain of those effects may be related to effects upon neurotransmitter release. See, for example, Sjak-shie et al., Brain Res., Vol. 624, pp. 295-298 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem., Vol. 43, pp. 1593-1598 (1984); Rapier et al., J. Neurochem., Vol. 50, pp. 1123-1130 (1988); Sandor et al., Brain Res.. Vol. 567, pp. 313-316 (1991) and Vizi, Br. J.
  • a pharmaceutical composition containing an active ingredient having nicotinic pharmacology which pharmaceutical composition is capable of eliciting neurotransmitter release within a subject in order to prevent or treat a neurological disorder.
  • nicotine reportedly potentiates the pharmacological behavior of certain pharmaceutical compositions used for the treatment of certain CNS disorders. See, Sanberg et al, Pharmacol. Biochem. & Behavior. Vol. 46, pp. 303-307 (1993); Harsing et al.. J. Neurochem., Vol. 59, pp. 48-54 (1993) and Hughes, Proceedings from Intl. Svmp. Nic. S40 (1994). Furthermore, various other beneficial pharmacological effects of nicotine have been proposed.
  • the present invention in one aspect, relates to 2- azabicyclo[2.2.1]hept-5-ene compounds.
  • Such compounds have a bicyclic functionality; and (i) the bridge of such functionality has a length of 1 carbon atom, (ii) the bicyclic functionality can have a C-C single bond or a C-C double bond positioned at its 5-6 position, and (iii) the nitrogen of the bicyclic functionality can possess a substituent group other than hydrogen, and (iv) the 3 position of the bicyclic functionality can possess a substituent positioned such that the compound can exist in either an endo or exo form.
  • the present invention in another aspect, relates to 2- azabicyclo[2.2.2]oct-5-ene compounds.
  • Such compounds have a bicyclic functionality; and (i) the bridge of such functionality has a length 2 carbon atoms, (ii) the bicyclic functionality can have a C-C single bond or a C-C double bond positioned at its 5-6 position, and (iii) the nitrogen of the bicyclic functionality can possess a substituent group other than hydrogen, and (iv) except when a C-C single bond exists at the 5-6 position of the bicyclic functionality, the 3 position of the bicyclic functionality can possess a substituent positioned such that the compound can exist in either an endo or exo form.
  • the present invention relates to a method for providing prevention or treatment of a central nervous system (CNS) disorder.
  • the method involves administering to a subject an effective amount of a compound of the present invention.
  • the compound can be administered in a free base form or in the form of a pharmaceutically acceptable salt.
  • the compound can be administered in the form of a racemic mixture or as an enantiomer.
  • the present invention in another aspect, relates to a pharmaceutical composition comprising an effective amount of a compound of the present invention.
  • Such a pharmaceutical composition incorporates a compound which has the capability of interacting with relevant nicotinic receptor sites of a subject, and hence has the capability of acting as a therapeutic in the prevention or treatment of a CNS disorder.
  • the compound can have a free base form or be in the form of a pharmaceutically acceptable salt.
  • the compound can be administered in the form of a racemic mixture or as an enantiomer.
  • the pharmaceutical compositions of the present invention are useful for the prevention and treatment of CNS disorders.
  • the pharmaceutical compositions provide therapeutic benefit to individuals suffering from certain CNS disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions have the potential to (i) exhibit nicotinic pharmacology and affect nicotinic receptors sites in the CNS (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases.
  • the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) not provide appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, and significant effects upon skeletal muscle).
  • the pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of CNS disorders.
  • X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, generally greater than 0.2 and even greater than 0.3; less than 0 and generally less than -0.1 ; or 0; as determined in accordance with Hansch et al., Chem. Rev.. Vol. 91, pp.
  • n is an integer which can range from 1 to 2;
  • R individually represents hydrogen or lower alkyl (e.g., alkyl containing one to five carbon atoms, such as methyl, ethyl or isopropyl), and preferably all R are hydrogen;
  • Z represents lower alkyl (e.g., alkyl containing one to five carbon atoms, such as methyl, ethyl or isopropyl);
  • A, A' and A" individually represent hydrogen, alkyl (e.g., lower straight chain or branched alkyl, including C, - C 7 , but preferably methyl or ethyl), or halo (e.g., F, Cl, Br or I), and
  • A" can represent an aromatic group-containing species, such as aryl, phenyl, pyridyl, arylalkyl (e.g., where the alkyl substituent contains 1 to 4 carbon atoms, and an exemplary arylalkyl
  • Y represents hydrogen, alkyl (e.g., alkyl containing 1 to 7 carbon atoms), or an aromatic group-containing species, such as aryl, phenyl, pyridyl, arylalkyl (e.g., where the alkyl substituent contains 1 to 4 carbon atoms, and an exemplary arylalkyl species is benzyl) or pyrimidyl.
  • Y is straight chain or branched alkyl containing 1 to about 4 carbon atoms (e.g., methyl or ethyl).
  • R' and R" are individually hydrogen or lower alkyl (e.g., alkyl containing one to five carbon
  • arylalkyl e.g., where the alkyl substituent contains 1 to 4 carbon atoms, and an exemplary arylalkyl species is benzyl
  • X represents a carbon atom bonded to a substituent species
  • that substituent species often has a sigma m value which is between about -0.3 and about 0.75. and frequently between about -0.25 and about 0.6.
  • A is hydrogen
  • A' is hydrogen
  • normally A" is hydrogen.
  • both A and A' are hydrogen; sometimes A and A * are hydrogen, and A" is chloro, methyl or ethyl; and often A, A' and A" are all hydrogen.
  • the dashed line is a C-C double bond
  • Y is a substituent other than hydrogen (e.g., alkyl containing 1 to 4 carbon atoms).
  • the dashed line is a C-C single bond
  • Y is hydrogen.
  • Representative compounds include (+/-)-3-exo and (+/-)-3-endo forms of 2-methyl-3-[3-(5- bromopyridyl)]-2-azabicyclo[2.2.1]hept-5-ene for which X is C-Br, A, A', A", R are H, n is 1, p is 0, Y is CH 3 , and the dashed line represents a C-C double bond.
  • Representative compounds include (+/-)-3-exo and (+/-)-3-endo_ forms of 2- methyl-3-(3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ene, for which the dashed line is a C-C double bond, Y is -CH 3 and n is 1.
  • Other representative compounds are (+/-)-3-exo and (+/-)-3-endo forms of 2-ethyl-3-(3-pyridyl)-2- azabicyclo[2.2.1]hept-5-ene, for which the dashed line is a C-C double bond, Y is -CH 2 -CH 3 and n is 1.
  • Another representative compound is the racemic form of 2-methyl-3- - 12 - (3-pyridyl)-2-azabicyclo[2.2.2]octane, for which the dashed line is a C-C single bond, Y is -CH 3 and n is 2.
  • Compounds of the present invention can be synthetically produced in a step-wise fashion. Pyridyl 3-carboxaldehydes and pyrimidyl 3- carboxaldehydes are provided. Compounds such as 4-methyl-3- pyridinecarboxaldehyde, 5 -methyl-3 -pyridinecarboxaldehyde, 4-phenyl-3- pyridinecarboxaldehyde, 5-phenyl-3-pyridinecarboxaldehyde, 6-phenyl-3- pyridinecarboxaldehyde, 4-chloro-3-pyridinecarboxaldehyde and 5-chloro-3- pyridinecarboxaldehyde can be prepared in accordance with the types of procedures set forth in Comins et al, Heterocycles.
  • Compounds such as 4-bromo-3 -pyridinecarboxaldehyde can be obtained by regiospecific lithiation of nicotinaldehyde followed by lithium/halogen exchange as reported by Kelly et al, Tetrahedron Letters. Vol. 34, p. 6173 (1993).
  • Compounds such as 2-chloro-3-pyridinecarboxaldehyde can be prepared by reduction of 2-chloro-3-cyanopyridine by Raney Nickel and formic acid as reported by Lynch et al, Can. J. Chem., Vol. 66, p. 420 (1988).
  • Pyridyl 3 -carboxaldehydes and pyrimidyl 3 -carboxaldehydes then each are converted to the appropriate Shiff base using techniques which are familiar to those skilled in the art of organic synthesis.
  • racemic mixtures of compounds of the present invention are provided by Diels Alder reaction with an appropriate cyclopentadiene.
  • pyridyl 3-carboxaldehydes and pyrimidyl 3- carboxaldehydes are converted to their corresponding bis-carbamates using techniques which are familiar to those skilled in the art of organic synthesis.
  • racemic mixtures of compounds of the present invention are provided by Diels Alder reaction with an appropriate cyclohexadiene.
  • ljhept- 5-ene is prepared from a mixture of isomers at a yield of 20% using silica gel chromatography ( 200-400 mesh ), eluting with 5% of methanol in chloroform as eluent, and such isomer has a migration value (R f ) of 0.41 when analyzed by thin layer chromatography, using a solvent system of chloroform-methanol (90:10,v/v).
  • R f migration value
  • (+/-V3 -Exo-2-benzyl-3 - (3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ene is prepared from a mixture of isomers at a yield of 13% using a silica gel chromatography ( 200-400 mesh ), eluting with 5% of methanol in chloroform as eluent, and such isomer has R ⁇ O.38 when analyzed by thin layer chromatography, using a solvent system of methanol- chloroform (5:95, v/v).
  • Racemic mixtures are provided, and the compounds of the present invention can be provided as enantiomers via chromatographic separation. Enantiomeric resolution of racemic compounds can be achieved by high performance liquid chromatography using beta-cyclodextrin bonded silica gel as the chiral stationary phase based on the method developed for nicotine and nornicotine analogs. See, Armstrong et al., Anal. Chem.. Vol. 60, p. 2120-2127 (1988).
  • Representative compounds of the present invention are (+/-)-3- endo-2-methyl-3-[3-(6-methylpyridyl)]-2-azabicyclo[2.2.1]hept-5-ene and(+/-)-3- e * o-2-methyl-3-[3-(6-methylpyridyl)]-2-azabicyclo[2.2. l]hept-5-ene which are prepared essentially in accordance with the following techniques.
  • Ethyl-6-methyl- 3-pyridinecarboxylate is prepared essentially in accordance with the techniques described by E. Leete et al, Phvtochemistrv. Vol.10, p. 2687 ( 1971) to afford 5g (83%o) of that compound.
  • 6-Methyl-3-pyridinemethylalcohol is prepared essentially in accordance with the techniques described in Nutaitis et al, Org. Prep. Proc. Int.. Vol. 24, pp.143-146 (1992) to afford 2.9 g (78%) of that compound.
  • Dimethyl sulfoxide (3.50 mL, 44 mmol) is added dropwise at -60°C, over a period of 5 min., to a solution of oxalyl chloride (2 mL. 22 mmol) in dry methylene chloride (50 mL).
  • the reaction mixture is stirred at -60°C for 2 min., then a solution of 6-methyl-3-pyridinemethylalcohol (2.5 g, 20.32 mmol) in dry methylene chloride (5 mL) is added over a 15 min. period and the resulting solution is stirred for 15 min. at -60°C.
  • Triethylamine 15mL is added and the solution is stirred for 5 additional minutes, followed by the addition of water (lOOmL).
  • the reaction mixture is allowed to warm to room temperature and extracted with chloroform ( 4x25 mL). The organic extracts are dried over anhydrous Na 2 SO 4 , filtered and evaporated on a rotary evaporator to give 2.5g of a thick syrup.
  • the pure compound, 6-methyl-3-pyridinecarboxaldehyde, (2.09, 85%) is obtained after column chromatography over silica gel (200-400 mesh) using chloroform-methanol (98:2, v/v) as eluent.
  • a mixture of 6-methyl-3- pyridinecarboxaldehyde ( 2.5g, 20.66mmol), methylamine ( 12mL, 2.0 M solution in tetrahydrofuran) and molecular sieves ( 3A, 5.0 g) are stirred for 12 hours under a nitrogen atmosphere. The reaction mixture is then filtered through celite.
  • the mixture is cooled to -78°C ( dry ice-acetone bath ) before addition of a solution of freshly distilled cyclopentadiene (2.4 mL. 26.9 mmol) in dry methylene chloride ( 5 mL ).
  • the reaction mixture is allowed to warm to ambient temperature overnight.
  • Chloroform ( 10 mL ) is added to the mixture, and the solution is filtered through a bed of Celite. The filtrate is evaporated to dryness and the resulting residue is dissolved by addition of a 10%> aqueous solution of sodium hydroxide.
  • the resulting solution is stirred for 10 min. and extracted with chloroform ( 4x10 mL ).
  • the present invention relates to a method for providing prevention of a CNS disorder to a subject susceptible to such a disorder, and for providing treatment to a subject suffering from a CNS disorder.
  • the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of the CNS disorder (i.e., provide protective effects), amelioration of the symptoms of the CNS disorder, and amelioration of the reoccurrence of the CNS disorder.
  • the method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore.
  • the present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore.
  • the majority of the compounds have either an endo or exo isomeric form.
  • the compounds can be employed as racemic mixtures or as enantiomers.
  • CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzlieimer " s type), Parkinsonism including Parkinson's disease. Huntington ' s chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
  • the pharmaceutical composition also can include various other components as additives or adjuncts.
  • exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, buffering agents, anti-inflammatory agents, anti-pyretics, time release binders, anaesthetics, steroids and corticosteroids.
  • Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition.
  • a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular CNS disorder.
  • the pharmaceutical compositions can be formulated to provide the desired formulation.
  • the manner in which the compounds are administered can vary.
  • the compounds can be administered by inhalation (e.g.. in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4.922,901 to Brooks et al.); topically (e.g.. in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g..).
  • inhalation e.g.. in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4.922,901 to Brooks et al.
  • topically e.g. in lotion form
  • orally e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within
  • each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
  • Exemplary methods for administering such compounds will be apparent to the skilled artisan.
  • the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule.
  • the compounds can be delivered transdermally using the types of patch technologies available from Ciba-Geigy Corporation and Alza Corporation.
  • the administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, such as a human being.
  • a warm-blooded animal such as a human being.
  • the time of day and the number of times per day that the pharmaceutical formulation is administered can vary. Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that affect the functioning of the CNS.
  • the dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers.
  • 'effective amount', 'therapeutic amount' or 'effective dose' is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.
  • an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to elicit neuropharmacological effects (e.g., elicit neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
  • Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder.
  • the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 mg / 24 hr. / patient.
  • the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg / 24 hr. / patient.
  • administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
  • the compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient.
  • the log P values of typical compounds useful in carrying out the present invention generally are greater than 0, often are greater than about 1 , and frequently are greater than about 1.5.
  • the log P values of such typical compounds generally are less than about 4, often are less than about 3.5, and frequently are less than about 3.
  • Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med. Chem.. Vol. 11, p. 1 (1968).
  • the compounds useful according to the method of the present invention have the ability to bind to, and in most circumstances, cause activation of, nicotinic cholinergic receptors of the brain of the patient. As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists.
  • the receptor binding constants of preferred compounds useful in carrying out the present invention generally exceed about
  • the receptor binding constants of such preferred compounds generally are less than about 10 uM, often are less than about 7 uM, and frequently are less than about
  • Receptor binding constants provide a measure of the ability of the compound to bind to half of the relevant receptor sites of certain brain cells of the patient. See. Cheng, et al.. Biochem. Pharmacol.. Vol. 22, pp. 3099-3108 (1973).
  • the compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic function by effectively eliciting neurotransmitter secretion from nerve ending preparations (i.e., synaptosomes). As such, such compounds have the ability to cause relevant neurons to release or secrete acetylcholine, dopamine, and other neurotransmitters.
  • nerve ending preparations i.e., synaptosomes
  • certain compounds useful in carrying out the present invention provide for the secretion of dopamine in amounts of at least about 10 percent, often at least about 20 percent, and frequently at least about 30 percent, of that elicited by an equal molar amount of S(-) nicotine.
  • the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, lack the ability to elicit activation of nicotinic receptors of human muscle to any significant degree.
  • the compounds of the present invention demonstrate poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from muscle preparations.
  • preferred compounds useful in carrying the present invention activate isotopic rubidium ion flux by less than 15 percent, often by less than 10 percent, and frequently by less than 5 percent, of that elicited by an equal molar amount of (S)-(-)-nicotine.
  • the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects.
  • a particular dose of compound resulting in prevention and/or treatment of a CNS disorder is essentially ineffective in eliciting activation of certain ganglionic-type nicotinic receptors.
  • This selectivity of the compounds of the present invention against those receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue.
  • Such compounds have poor ability to cause isotopic rubidium ion flux through nicotinic receptors in cell preparations derived from the adrenal gland.
  • preferred compounds useful in carrying the present invention activate isotopic rubidium ion flux by less than 15 percent, often by less than 10 percent, and frequently by less than 5 percent, of that elicited by an equal molar amount of (S)-(-)-nicotine.
  • Compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of the progression of CNS disorders, amelioration of the symptoms of CNS disorders, and amelioration to some degree of the reoccurrence of CNS disorders.
  • effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as demonstrated by increased effects relating to the cardiovascular system, and effects to skeletal muscle.
  • administration of compounds of the present invention provides a therapeutic window in which treatment of certain CNS disorders is provided, and side effects are avoided. That is, an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
  • effective administration of a compound of the present invention resulting in treatment of CNS disorders occurs upon administration of less than 1/5, often less than 1/10, and even less than 1/100, that amount sufficient to cause any side effects to a significant degree.
  • the resulting thick syrup was purified by column chromatography over silica gel (200-400 mesh ) using acetonitrile in chloroform (1 :7, v/v) as eluant and afforded 2.60 g ( 67%) of a mixture of (+/-)-endo and (+/-)-exo isomers (ratio 60:40, respectively). This mixture was used in the next step without separation of the isomers.
  • Sample No. 2 is (+/-)-exo-3-(3-pyridyl)-2-azabicyclo[2.2.2]oct-5- ene fumarate which is prepared essentially in accordance with the following techniques.
  • (+/-VExo-3-(3-pyridvD-2-azabicyclor2.2.2]oct-5-ene (VI).
  • fumaric acid 124mg.1.068. mmol
  • the resulting suspension was sonicated until complete dissolution occured.
  • the solvent was removed on a rotary evaporator to give a colorless syrup which was crystallized from absolute ethanol to yield 165mg ( 74%) of compound (VII).
  • Mp 167°-169° C.
  • Sample No. 3 is (+/-)-endo-2-methyl-3-(3-pyridyl)-2- azabicyclo[2.2.2]oct-5-ene fumarate which is prepared essentially in accordance with the following techniques. (+/-)-Endo-2-methyl-3-(3-pyridyl)-2-azabicvclo[2.2.21oct-5-ene (VIII).
  • (+/-)-Exo-2-methyl-3-(3-pyridyl)-2-azabicylor2.2.21oct-5-ene X.
  • Formic acid (5 mL, 95-97 %>) and formaldehyde (0.5 mL, 37% in water) were added to (+/-)-exo 3-(3-pyridyl)-2-azabicyclo[2.2.2]oct-5-ene (VI) (150 mg, 0.75mmol) and the mixture refluxed for 24 hours under nitrogen.
  • Sample No. 5 is (+/-)-3-(3-pyridyl)-2-azabicyclo[2.2.2]octane fumarate which was prepared essentially in accordance with the following techniques.
  • (+/-)-3-(3-pyridyl)-2-carboethoxy-2-azabicvclo[2.2.21octane (XII) A solution of the (+/-)-endo and (+/-)-exo isomers of 3-(3-pyridyl)-2- carboethoxy-2-azabicyclo[2.2.2]oct-5-ene. compound (II). (750 mg, 2.90 mmol) in glacial acetic acid (0.5mL) and Pd/C (10 %) was shaken under a H 2 atmosphere in a Parr apparatus for 2 hours. The catalyst was removed by Alteration over a bed of Celite and the filterate was basified by addition of a solution of 40%) of NaOH in water.
  • (+/-)-3-(3-pyridyl)-2-carboethoxy-2-azabicyclo[2.2.2]octane (XII) 500 mg, 1.92 mmol was dissolved in a solution of 20% (w/v) NaOH in absolute ethanol (10 mL) and refluxed for 24 h. The organic solvent was evaporated on a rotary evaporator. The pH of the basic residue was adjusted to 9 by addition of a solution of 2N HCl in water and was extracted with ethyl acetate (4x10 mL). The organic extracts were dried over anhydrous K 2 CO 3 and concentrated.
  • fumaric acid 124mg, 1.062mmol
  • Mp * 180°C (decomposition).
  • Sample No . 6 is (+/-)-2-methyl-3 -(3 -pyridyl)-2- azabicyclo[2.2.2]octane fumarate which was prepared essentially in accordance with the following techniques.
  • Sample No. 7 is (+/-)-endo-2-ethvl-3-(3-pvridvl)-2- azabicyclo[2.2.1]hept-5-ene which is prepared essentially in accordance with the following techniques.
  • Sample No. 8 is (+/-)-endo_-2-(p-methoxybenzyl)-3-(3-pyridyl)-2- azabicyclo[2.2.1]hept-5-ene which is prepared essentially in accordance with the following techniques.
  • Sample No. 9 is (+/-)-endo-2-benzyl-3-(3-pyridyl)-2- azabicyclo[2.2.1]hept-5-ene which is prepared essentially in accordance with the following techniques. N-(3-pyridylidene)-benzylamine (XXIII).
  • Sample No. 10 is (+/-)-endo-2-methvl-3-(3-pyridyl)-2- azabicyclo[2.2.1]hept-5-ene which is prepared essentially in accordance with the following techniques. N-(3-Pyridylidene)methylamine (XXVI).
  • (+/-vExo-2-methyl-3-(3-pyridyl)-2-azabicvclor2.2.1 lhept-5-ene XXVIII.
  • Sample No. 12 is (+/-)-endo_-2-methyl-3-[3-(5-bromopyridyl)]-2- azabicyclo[2.2.1]hept-5-ene which is prepared essentially in accordance with the following techniques.
  • Sample No. C-l was provided. This sample is (S)-(-)-nicotine, which has been reported to have demonstrated a positive effect towards the treatment of various CNS disorders.
  • Rats Males or females were killed by decapitation following anesthesia with 70%>
  • Brains were removed and placed on an ice-cold platform. The cerebellum was removed and the remaining tissue was placed in 10 volumes (weigh volume) of ice-cold buffer (Krebs-Ringers HEPES: NaCl, 118 mM; KC1. 4.8 mM; CaCl 2 , 2.5 mM; MgSO 4 , 1.2 mM; HEPES, 20 mM; pH to 7.5 with NaOH) and homogenized with a glass- Teflon tissue grinder. The resulting homogenate was centrifuged at 18,000 x g for 20 min. and the resulting pellet was resuspended in 20 volumes of water. After 60 min.
  • ice-cold buffer Karl-Ringers HEPES: NaCl, 118 mM; KC1. 4.8 mM; CaCl 2 , 2.5 mM; MgSO 4 , 1.2 mM; HEPES, 20 mM; pH to 7.5 with NaOH
  • the pellet obtained was resuspended in buffer to a final concentration of approximately 5 mg protein/ml. Protein was determined by the method of Lowry et al., J. Biol. Chem.. Vol. 193, pp. 265-275 (1951), using bovine serum albumin as the standard.
  • L-[ J H]nicotine was measured using a modification of the method of Romano et al., Science, Vol. 210, pp. 647-650 (1980) as described previously by Marks et al., Mol. Pharmacol .. Vol. 30, pp. 427-436 (1986).
  • the L-[ 3 H]nicotine used in all experiments was purified chromatographically by the method of Romm, et al., Life Sci.. Vol. 46, pp. 935- 943 (1990).
  • the binding of L-[ 3 H]nicotine was measured using a 2 hr. incubation at 4 °C.
  • Incubations contained about 500 ug of protein and were conducted in 12 mm x 75 mm polypropylene test tubes in a final incubation volume of 250 ul.
  • the incubation buffer was Krebs-Ringers HEPES containing 200 mM TRIS buffer, pH 7.5.
  • the binding reaction was terminated by filtration of the protein containing bound ligand onto glass fiber filters (Micro Filtration Systems) that had been soaked in buffer containing 0.5 percent polyethyleneimine. Filtration vacuum was -50 to -100 torr. Each filter was washed five times with 3 ml of ice-cold buffer.
  • the filtration apparatus was cooled to 2 °C before use and was kept cold through the filtration process.
  • Nonspecific binding was determined by inclusion of 10 uM nonradioactive nicotine in the incubations.
  • the inhibition of L- Hjnicotine binding by test compounds was determined by including one of eight different concentrations of the test compound in the incubation.
  • Inhibition profiles were measured using 10 nM L- [ * 1H]nicotine and IC50 values were estimated as the concentration of compound that inhibited 50 percent of specific L- H]nicotine binding.
  • Inhibition constants (Ki values) reported in nM, were calculated from the IC50 values using the method of Cheng et al., Biochem. Pharmacol.. Vol. 22, pp. 3099-3108 (1973).
  • Dopamine release was measured by preparing synaptosomes from the striatal area of rat brain obtained from Sprague-Dawley rats generally according to the procedures set forth by Nagy et al., J. Neurochem.. Vol. 43, pp.
  • the synaptosomes were recovered above the 16 percent layer with a Pasteur pipette, diluted with 8 ml of perfusion buffer (128 mM NaCl, 2.4 mM KC1, 3.2 mM CaCl 2 , 1.2 mM KH 2 PO , 1.2 mM MgS0 4 , 25 mM HEPES pH 7.4, 10 mM dextrose, 1 mM ascorbate, 0.01 mM pargyline), and centrifuged at 15,000 x g for 20 min. The new pellet was collected and re-suspended in perfusion buffer. The synaptosome suspension was incubated for 10 min.
  • Synaptosomes were washed with perfusion buffer for a minimum of 20 min. before addition of the ligand. After the addition of 0.2 ml of a solution containing various concentrations of ligand, the perfusate was collected into scintillation vials at 1 min. intervals and the dopamine released was quantified by scintillation counting. Peaks of radioactivity released above background were summed and the average basal release during that time was subtracted from the total. Release was expressed as a percentage of release obtained with an equal concentration of (S)-(-)-nicotine. Determination of Log P
  • Log P values (log octanol/water partition coefficient), which have been used to assess the relative abilities of compounds to pass across the blood- brain barrier (Hansch, et al., J. Med. Chem.. Vol. 11, p. 1 (1968)), were calculated according to the methods described by Hopfinger, Conformational Properties of Macromolecules, Academic Press (1973) using Cerius 2 software package by Molecular Simulations, Inc.
  • Human muscle activation was established on the human clonal line TE671/RD which is derived from an embryonal rhabdomyosarcoma (Stratton et al., Carcinogen. Vol. 10, pp. 899-905 (1989)). As evidenced through pharmacological (Lukas, J. Pharmacol. Exp. Ther.. Vol. 251, pp. 175-182 (1989)), electrophysiological (Oswald et al, Neurosci. Lett.. Vol. 96, pp. 207-212 (1989)), and molecular biological studies (Luther et al., J. Neurosci., Vol. 9, pp.
  • Nicotinic acetylcholine receptor (nAChR) function was assayed using 86Rb + efflux according to a method described by Lukas et al., Anal. Biochem.. Vol. 175, pp. 212-218 (1988).
  • the maximal activation for individual compounds (Emax) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
  • N i c o t i n i c acetylcholine receptor (nAChR) function was assayed using 86J * - - , + efflux according to a method described by Lukas et al., Anal. Biochem.. Vol. 175, pp. 212-218 (1988).
  • Cells were plated in 35-mm diameter wells of 6-well dishes for at least 48 hours and loaded for at least 4 hours at 37 °C in a medium containing serum, and 1 ⁇ Ci/ml °°Rb + .
  • Sample Nos. 2, 4 and 11 which have an exo form, exhibit good high affinity binding to CNS nicotinic receptors.
  • Sample Nos. 5 and 6 which have neither an exo nor endo form, exhibit good high affinity binding to CNS nicotinic receptors.
  • Sample No. 10 which has an endo form, exhibits good high affinity binding to CNS nicotinic receptors.
  • Sample Nos. 8 and 9 induce dopamine release and exhibit desirably low effects at muscle sites and ganglionic sites.
  • Sample Nos. 4, 5, 6 and 10 exhibit good high affinity binding to CNS nicotinic receptors and exhibit desirably low effects at muscle sites and ganglionic sites.
  • the data in Table I indicate that the compounds have the capability of passing the blood-brain barrier by virtue of their favorable logP values. Certain compounds exhibit binding to high affinity CNS nicotinic receptors as indicated by their low binding constants. Certain compounds induce activation of CNS nicotinic receptors of a subject and cause neurotransmitter release, and thereby have the capability of demonstrating known nicotinic pharmacology. Thus, the data indicate that such compounds have the capability of being useful in treating CNS disorders involving nicotinic cholinergic systems. Furthermore, the data indicate that certain compounds do not cause any appreciable effects at muscle sites and ganglionic sites, thus indicating the potential for a lack of undesirable side effects in subjects receiving administration of those compounds.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention permet de traiter les patients prédisposés à ou atteints de troubles du système nerveux central (par exemple, les maladies neurodégénératives, dont la démence présénile, la démence sénile de type Alzheimer, le parkinsonisme dont la maladie de Parkinson, et autres pathologies du SNC, dont le trouble déficitaire de l'attention, la schizophrénie et la maladie de Gilles de la Tourette) en leur administrant une dose efficace de composés de 2-azabicyclo [2.2.1] hept-5-ène et 2-azabicyclo [2.2.2] oct-5-ène. Parmi les composés exemplaires on trouve les formes (+/-)-3-exo et (+/-)-3-endo de 2-méthyl-3-(3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ène, les formes (+/)-3-exo et (+/-)-3-endo de 2-éthyl-3-(3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ène, les formes (+/-)-3-exo et (+/-)-3-endo de 2-benzyl-3-(3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ène, les formes (+/-)-3-exo et (+/-)-3-endo de 2-para-anisyl-3-(3-pyridyl)-2-azabicyclo[2.2.1]hept-5-ène, les formes (+/-)-3-exo et (+/-)-3-endo de 3-(3-pyridyl)-2-azabicyclo [2.2.2]oct-5-ène, les formes (+/-)-3-exo et (+/-)-3-endo de 3-(3-pyridyl)-2-azabicyclo[2.2.2.]oct-5-ène, les formes (+/-)-3-exo et (+/-)-3-endo de 2-méthyl-3-(3-pyridyl)-2-azabicyclo[2.2.2.]oct-5-ène, la forme racémique de 3-(3-pyridyl)-2-azabicyclo [2.2.2.]octane, et la forme racémique de 2-méthyl-3-(3-pyridyl)-2-azabicylo [2.2.2]octane.
PCT/US1996/004536 1995-05-17 1996-04-03 Compositions pharmaceutiques destinees a la prophylaxie et au traitement des troubles du systeme nerveux central WO1996036637A1 (fr)

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Cited By (18)

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WO1998048801A1 (fr) * 1997-04-26 1998-11-05 Sumitomo Pharmaceuticals Co., Ltd. Composes 2-azabicyclo
WO1999000385A1 (fr) * 1997-06-30 1999-01-07 R.J. Reynolds Tobacco Company Derives 3-pyridyl-1-aza-bicyclo-alcane destines a la prevention et au traitement des troubles du systeme nerveux central
US5859024A (en) * 1996-05-13 1999-01-12 Zeneca Limited Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives
US5912254A (en) * 1996-11-15 1999-06-15 Zeneca Limited Bicycle amine derivatives
US5922732A (en) * 1995-05-24 1999-07-13 Zeneca Limited Bicyclic amines
WO1999051601A1 (fr) * 1998-04-02 1999-10-14 R.J. Reynolds Tobacco Company Composes aza tricycliques
US5968947A (en) * 1996-11-26 1999-10-19 Zeneca Limited Bicyclic amine derivatives
WO1999065876A1 (fr) * 1998-06-16 1999-12-23 R.J. Reynolds Tobacco Company Amines olefiniques a substitution aryle et leur utilisation comme agonistes de recepteurs cholinergiques
US6093726A (en) * 1996-11-26 2000-07-25 Zeneca Limited Bicyclic amine derivatives
WO2000075110A1 (fr) * 1999-06-07 2000-12-14 Targacept, Inc. Compositions pharmaceutiques et methodes d'utilisation
US6492399B1 (en) 1998-06-16 2002-12-10 Targacept, Inc. Pharmaceutical compositions and methods for use
US6525065B1 (en) 1997-06-30 2003-02-25 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
WO2005037832A2 (fr) * 2003-10-15 2005-04-28 Targacept, Inc. Compositions pharmaceutiques et methodes destinees au soulagement de la douleur et au traitement de troubles du systeme nerveux central
US6958399B2 (en) 1998-06-16 2005-10-25 Targacept, Inc. Compounds capable of activating cholinergic receptors
US6979695B2 (en) 1996-04-23 2005-12-27 Targacept, Inc. Compounds capable of activating cholinergic receptors
US7060826B2 (en) 1998-06-16 2006-06-13 Targaeept, Inc. Compounds capable of activating cholinergic receptors
US7790757B2 (en) 1998-06-16 2010-09-07 Targacept, Inc. Compounds capable of activating cholinergic receptors
CN115698002A (zh) * 2020-06-24 2023-02-03 菲利普莫里斯生产公司 用于寄生虫控制的组合物和方法

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US5278176A (en) * 1992-08-21 1994-01-11 Abbott Laboratories Nicotine derivatives that enhance cognitive function
WO1995003306A1 (fr) * 1993-07-22 1995-02-02 E.I. Du Pont De Nemours And Company Heterocycles azacycliques arthropodicides
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EP0412798A2 (fr) * 1989-08-08 1991-02-13 MERCK SHARP & DOHME LTD. Pyridines substitués, leur préparation, formulations et application anti-démence
US5278176A (en) * 1992-08-21 1994-01-11 Abbott Laboratories Nicotine derivatives that enhance cognitive function
WO1995003306A1 (fr) * 1993-07-22 1995-02-02 E.I. Du Pont De Nemours And Company Heterocycles azacycliques arthropodicides
WO1995007078A1 (fr) * 1993-09-10 1995-03-16 Cytomed, Inc. Epibatidine et ses derives utilises en tant qu'agonistes et antagonistes de recepteurs cholinergiques

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US6207676B1 (en) 1995-05-24 2001-03-27 Zeneca Limited Bicyclic amines
US5922732A (en) * 1995-05-24 1999-07-13 Zeneca Limited Bicyclic amines
US6573275B1 (en) 1995-05-24 2003-06-03 Syngenta Limited Bicyclic amines
US7045538B2 (en) 1996-04-23 2006-05-16 Targacept, Inc. Compounds capable of activating cholinergic receptors
US6979695B2 (en) 1996-04-23 2005-12-27 Targacept, Inc. Compounds capable of activating cholinergic receptors
US5859024A (en) * 1996-05-13 1999-01-12 Zeneca Limited Insecticidal, acaricidal or nematicidal 3-cyano-8-azabicyclo 3.2.1!octane derivatives
US6066646A (en) * 1996-11-15 2000-05-23 Zeneca Limited Bicyclic amine derivatives
US5912254A (en) * 1996-11-15 1999-06-15 Zeneca Limited Bicycle amine derivatives
US5968947A (en) * 1996-11-26 1999-10-19 Zeneca Limited Bicyclic amine derivatives
US6093726A (en) * 1996-11-26 2000-07-25 Zeneca Limited Bicyclic amine derivatives
US6174894B1 (en) 1996-11-26 2001-01-16 Zeneca Limited Bicyclic amine derivatives
US6177442B1 (en) 1996-11-26 2001-01-23 Zeneca Limited Bicyclic amine derivatives
US6291474B1 (en) 1996-11-26 2001-09-18 Zeneca Limited Bicyclic amine derivatives
WO1998048801A1 (fr) * 1997-04-26 1998-11-05 Sumitomo Pharmaceuticals Co., Ltd. Composes 2-azabicyclo
WO1999000385A1 (fr) * 1997-06-30 1999-01-07 R.J. Reynolds Tobacco Company Derives 3-pyridyl-1-aza-bicyclo-alcane destines a la prevention et au traitement des troubles du systeme nerveux central
US6525065B1 (en) 1997-06-30 2003-02-25 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
WO1999051601A1 (fr) * 1998-04-02 1999-10-14 R.J. Reynolds Tobacco Company Composes aza tricycliques
US6492399B1 (en) 1998-06-16 2002-12-10 Targacept, Inc. Pharmaceutical compositions and methods for use
JP2008255122A (ja) * 1998-06-16 2008-10-23 Targacept Inc アリール置換オレフィンアミンと、コリン受容体アゴニストとしてのアリール置換オレフィンアミンの使用
US8288420B2 (en) 1998-06-16 2012-10-16 Targacept, Inc. Compounds capable of activating cholinergic receptors
US6958399B2 (en) 1998-06-16 2005-10-25 Targacept, Inc. Compounds capable of activating cholinergic receptors
US7790757B2 (en) 1998-06-16 2010-09-07 Targacept, Inc. Compounds capable of activating cholinergic receptors
WO1999065876A1 (fr) * 1998-06-16 1999-12-23 R.J. Reynolds Tobacco Company Amines olefiniques a substitution aryle et leur utilisation comme agonistes de recepteurs cholinergiques
US7060826B2 (en) 1998-06-16 2006-06-13 Targaeept, Inc. Compounds capable of activating cholinergic receptors
JP2008260774A (ja) * 1998-06-16 2008-10-30 Targacept Inc アリール置換オレフィンアミンと、コリン受容体アゴニストとしてのアリール置換オレフィンアミンの使用
US7307092B2 (en) 1998-06-16 2007-12-11 Targacept, Inc. Compounds Capable of Activating Cholinergic Receptors
WO2000075110A1 (fr) * 1999-06-07 2000-12-14 Targacept, Inc. Compositions pharmaceutiques et methodes d'utilisation
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
JP2007533641A (ja) * 2003-10-15 2007-11-22 ターガセプト，インコーポレイテッド 疼痛緩和および中枢神経系障害治療のためのアザビシクロ化合物
WO2005037832A2 (fr) * 2003-10-15 2005-04-28 Targacept, Inc. Compositions pharmaceutiques et methodes destinees au soulagement de la douleur et au traitement de troubles du systeme nerveux central
US7897611B2 (en) 2003-10-15 2011-03-01 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
WO2005037832A3 (fr) * 2003-10-15 2005-06-16 Targacept Inc Compositions pharmaceutiques et methodes destinees au soulagement de la douleur et au traitement de troubles du systeme nerveux central
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