CA2333951A1 - Method for treating neurodegenerative disorders - Google Patents
Method for treating neurodegenerative disorders Download PDFInfo
- Publication number
- CA2333951A1 CA2333951A1 CA002333951A CA2333951A CA2333951A1 CA 2333951 A1 CA2333951 A1 CA 2333951A1 CA 002333951 A CA002333951 A CA 002333951A CA 2333951 A CA2333951 A CA 2333951A CA 2333951 A1 CA2333951 A1 CA 2333951A1
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- alkyl
- disease
- hydrogen
- aralkyl
- aryl
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- 238000000034 method Methods 0.000 title claims abstract 23
- 208000015122 neurodegenerative disease Diseases 0.000 title claims 6
- 150000001875 compounds Chemical class 0.000 claims abstract 19
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 claims abstract 15
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 claims abstract 15
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims abstract 9
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims abstract 9
- 230000003993 interaction Effects 0.000 claims abstract 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 21
- 229910052739 hydrogen Inorganic materials 0.000 claims 21
- 239000001257 hydrogen Substances 0.000 claims 21
- 125000003710 aryl alkyl group Chemical group 0.000 claims 20
- 125000001424 substituent group Chemical group 0.000 claims 20
- 125000003118 aryl group Chemical group 0.000 claims 14
- 150000002431 hydrogen Chemical group 0.000 claims 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 10
- 125000003342 alkenyl group Chemical group 0.000 claims 10
- 125000002757 morpholinyl group Chemical group 0.000 claims 9
- 125000003386 piperidinyl group Chemical group 0.000 claims 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 9
- 208000024827 Alzheimer disease Diseases 0.000 claims 7
- 125000000217 alkyl group Chemical group 0.000 claims 7
- 239000000651 prodrug Substances 0.000 claims 7
- 229940002612 prodrug Drugs 0.000 claims 7
- 150000003839 salts Chemical class 0.000 claims 7
- 206010012289 Dementia Diseases 0.000 claims 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 5
- 125000003545 alkoxy group Chemical group 0.000 claims 5
- -1 diphenylphosphinyl Chemical group 0.000 claims 5
- 229910052736 halogen Inorganic materials 0.000 claims 5
- 150000002367 halogens Chemical group 0.000 claims 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 4
- 125000002785 azepinyl group Chemical group 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 125000004193 piperazinyl group Chemical group 0.000 claims 4
- 125000003107 substituted aryl group Chemical group 0.000 claims 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 4
- POPPVIRYGJQIOF-UHFFFAOYSA-N 2-acetyloxyethyl(trimethyl)azanium;3-(1-methylpyrrolidin-2-yl)pyridine Chemical compound CC(=O)OCC[N+](C)(C)C.CN1CCCC1C1=CC=CN=C1 POPPVIRYGJQIOF-UHFFFAOYSA-N 0.000 claims 3
- 102000009660 Cholinergic Receptors Human genes 0.000 claims 3
- 108010009685 Cholinergic Receptors Proteins 0.000 claims 3
- 208000027747 Kennedy disease Diseases 0.000 claims 3
- 208000003954 Spinal Muscular Atrophies of Childhood Diseases 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 208000002320 spinal muscular atrophy Diseases 0.000 claims 3
- 208000033526 Proximal spinal muscular atrophy type 3 Diseases 0.000 claims 2
- 201000004810 Vascular dementia Diseases 0.000 claims 2
- 208000006269 X-Linked Bulbo-Spinal Atrophy Diseases 0.000 claims 2
- 206010002022 amyloidosis Diseases 0.000 claims 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 2
- 230000007850 degeneration Effects 0.000 claims 2
- 201000004815 juvenile spinal muscular atrophy Diseases 0.000 claims 2
- 238000012544 monitoring process Methods 0.000 claims 2
- 208000005264 motor neuron disease Diseases 0.000 claims 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 2
- 208000032527 type III spinal muscular atrophy Diseases 0.000 claims 2
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 206010059245 Angiopathy Diseases 0.000 claims 1
- 208000036487 Arthropathies Diseases 0.000 claims 1
- 206010003591 Ataxia Diseases 0.000 claims 1
- 102000007371 Ataxin-3 Human genes 0.000 claims 1
- 201000006474 Brain Ischemia Diseases 0.000 claims 1
- 206010006542 Bulbar palsy Diseases 0.000 claims 1
- 208000029402 Bulbospinal muscular atrophy Diseases 0.000 claims 1
- 206010068597 Bulbospinal muscular atrophy congenital Diseases 0.000 claims 1
- 206010008120 Cerebral ischaemia Diseases 0.000 claims 1
- 208000033647 Classic progressive supranuclear palsy syndrome Diseases 0.000 claims 1
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims 1
- 201000010374 Down Syndrome Diseases 0.000 claims 1
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims 1
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 1
- 208000003736 Gerstmann-Straussler-Scheinker Disease Diseases 0.000 claims 1
- 206010072075 Gerstmann-Straussler-Scheinker syndrome Diseases 0.000 claims 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 claims 1
- 206010019196 Head injury Diseases 0.000 claims 1
- 208000023105 Huntington disease Diseases 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 claims 1
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- 208000034800 Leukoencephalopathies Diseases 0.000 claims 1
- 208000009829 Lewy Body Disease Diseases 0.000 claims 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 claims 1
- 208000019090 Machado-Joseph disease type 3 Diseases 0.000 claims 1
- 208000027382 Mental deterioration Diseases 0.000 claims 1
- 206010027374 Mental impairment Diseases 0.000 claims 1
- 201000002795 Muckle-Wells syndrome Diseases 0.000 claims 1
- 208000034578 Multiple myelomas Diseases 0.000 claims 1
- 208000001089 Multiple system atrophy Diseases 0.000 claims 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims 1
- 206010033885 Paraparesis Diseases 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims 1
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 1
- 208000032319 Primary lateral sclerosis Diseases 0.000 claims 1
- 102000029797 Prion Human genes 0.000 claims 1
- 108091000054 Prion Proteins 0.000 claims 1
- 208000024777 Prion disease Diseases 0.000 claims 1
- 208000032225 Proximal spinal muscular atrophy type 1 Diseases 0.000 claims 1
- 208000021811 Sandhoff disease Diseases 0.000 claims 1
- 208000009106 Shy-Drager Syndrome Diseases 0.000 claims 1
- 208000002548 Spastic Paraparesis Diseases 0.000 claims 1
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 claims 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 claims 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 claims 1
- 208000032859 Synucleinopathies Diseases 0.000 claims 1
- 208000022292 Tay-Sachs disease Diseases 0.000 claims 1
- 208000000323 Tourette Syndrome Diseases 0.000 claims 1
- 206010044688 Trisomy 21 Diseases 0.000 claims 1
- 206010046298 Upper motor neurone lesion Diseases 0.000 claims 1
- 206010063661 Vascular encephalopathy Diseases 0.000 claims 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims 1
- 208000026481 Werdnig-Hoffmann disease Diseases 0.000 claims 1
- 230000002776 aggregation Effects 0.000 claims 1
- 238000004220 aggregation Methods 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 210000000601 blood cell Anatomy 0.000 claims 1
- 230000006931 brain damage Effects 0.000 claims 1
- 231100000874 brain damage Toxicity 0.000 claims 1
- 208000029028 brain injury Diseases 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 claims 1
- 230000001684 chronic effect Effects 0.000 claims 1
- 208000010877 cognitive disease Diseases 0.000 claims 1
- 230000001054 cortical effect Effects 0.000 claims 1
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 claims 1
- 230000003412 degenerative effect Effects 0.000 claims 1
- 208000017004 dementia pugilistica Diseases 0.000 claims 1
- 125000004663 dialkyl amino group Chemical group 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 230000003073 embolic effect Effects 0.000 claims 1
- 230000002124 endocrine Effects 0.000 claims 1
- 201000006061 fatal familial insomnia Diseases 0.000 claims 1
- 210000001652 frontal lobe Anatomy 0.000 claims 1
- 238000001631 haemodialysis Methods 0.000 claims 1
- 230000000322 hemodialysis Effects 0.000 claims 1
- 208000008675 hereditary spastic paraplegia Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 238000007917 intracranial administration Methods 0.000 claims 1
- 206010023497 kuru Diseases 0.000 claims 1
- 201000010901 lateral sclerosis Diseases 0.000 claims 1
- 230000003902 lesion Effects 0.000 claims 1
- 201000000564 macroglobulinemia Diseases 0.000 claims 1
- 230000002503 metabolic effect Effects 0.000 claims 1
- 210000002569 neuron Anatomy 0.000 claims 1
- 230000005015 neuronal process Effects 0.000 claims 1
- 229960002715 nicotine Drugs 0.000 claims 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 claims 1
- 208000001282 primary progressive aphasia Diseases 0.000 claims 1
- 238000004393 prognosis Methods 0.000 claims 1
- 208000032207 progressive 1 supranuclear palsy Diseases 0.000 claims 1
- 201000002241 progressive bulbar palsy Diseases 0.000 claims 1
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 claims 1
- 201000000196 pseudobulbar palsy Diseases 0.000 claims 1
- 102000005962 receptors Human genes 0.000 claims 1
- 108020003175 receptors Proteins 0.000 claims 1
- 238000012216 screening Methods 0.000 claims 1
- 230000001148 spastic effect Effects 0.000 claims 1
- 208000003755 striatonigral degeneration Diseases 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000001732 thrombotic effect Effects 0.000 claims 1
- 208000032471 type 1 spinal muscular atrophy Diseases 0.000 claims 1
- 230000000626 neurodegenerative effect Effects 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
- C07F9/32—Esters thereof
- C07F9/3258—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3282—Esters with hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Abstract
The invention is directed to a method of treating a neurodegenerative disord er in a subject in need thereof which comprises administering to the subject an amount of a compound effective to inhibit the interaction of amyloid-beta wi th alpha-7 nicotinic acetylcholine receptors.
Claims (27)
1.A method of treating a neurodegenerative disorder in a subject in need thereof which comprises administering to the subject an amount of a compound effective to inhibit the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
2. The method of Claim 1, wherein the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
3. The method of Claim 2, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohtfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica or frontal lobe dementia, neurodegenerative disorders resulting from cerebral ischemia or infaction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, nonneuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic and cardiac-related amyloidosis, chronic hemodialysis arthropathy, or Finnish and Iowa amyloidosis.
4. The method of Claim 3, wherein the amyloid beta peptide is A.beta.1-42..
5. The method of Claim 3, wherein the neurodegenerative disorder is Alzheimer's disease.
6. The method of Claim 5, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by binding to A.beta.1-42.
7. The method of Claim 3, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by binding to human alpha-7 nicotinic acetylcholine receptors.
8. The method of Claim 3, wherein the compound inhibits the binding of A.beta.1-42 with the human alpha-7 nicotinic acetylcholine receptor by inhibiting aggregation of amyloid beta peptides.
9. The method of Claim 5, wherein the compound is of the formula I
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C8 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-6alkyl, C1-C6 alkoxycarbonylC1-C8 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C8 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-6alkyl, C1-C6 alkoxycarbonylC1-C8 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
10. A method of treating and/or preventing dementia in an Alzheimer's disease patient which comprises administering to the subject a therapeutically effective amount of a compound which inhibits the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
11. The method of Claim 10, wherein the amyloid beta peptide is A.beta.l-42 and the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
12. The method of Claim 11, wherein the compound is of the formula I
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6 are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
13. A method of improving memory and/or of halting the progression of mental deterioration in an Alzheimer's disease patient which comprises administering to the subject a therapeutically effective amount of a compound to inhibit the binding of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
14. The method of Claim 13, wherein the amyloid beta peptide is A.beta.1-42 and the alpha-7 nicotinic acetylcholine receptors are human alpha-7 nicotinic acetylcholine receptors.
15. The method of Claim 14, wherein the compound is of the formula I
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
16. A method for identifying compounds which are useful for the treatment of neurodegenerative disorders involving screening test compounds for their ability to block the interaction of a peptide selected from the group consisting of 125¦-A.beta.1-40 A.beta.1-40 and A.beta.1-42 with nicotine acetylcholine receptors.
17. The method of Claim 16, wherein the nicotine acetycholine receptors are human alpha-7, human alpha-8, and/or human alpha-9 nicotinic acetylcholine receptors.
18. The method of Claim 17, wherein the nicotine acetylcholine receptors are human alpha-7 nicotine acetylcholine receptors.
19. The method of Claim 18, wherein the peptide is 124¦-A.beta.1-40.
20. A compound of the formula I:
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C1-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C71-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
wherein R1 is hydrogen or C1-C4 alkyl;
R2 is selected from hydrogen, C1-C6 alkyl, aryl or C1-C10 aralkyl;
R3 is selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkylC1-C6 alkyl, C1-C6 alkoxycarbonylC1-C6 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C71-C10 aralkyl wherein the substituent on the aryl or aralkyl are one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl and unsubstituted or substituted C1-C6 alkoxy wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six-membered heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl;
R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl; and R5 and R6s are each independently selected from hydrogen, C1-C6 alkyl, C3-C10 alkenyl, C1-C8 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
21. The compound of Claim 20, wherein R1, is hydrogen;
R2 is selected from hydrogen or C1-C4 alkyl;
R3 is selected from C1-C4 alkyl, C3-C10 alkenyl, C5-C6 cycloalkylC1-C4 6 alkyl, C1-C6 alkoxycarbonylC1-C4 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aralkyl are one or two substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl and unsubstituted or substituted C1-C4 alkoxy wherein the substituents on the alkoxy are one or two substituents independently selected from amino, C1-C4 alkylamino, C1-C4 dialkylamino, pyrrolidinyl, or piperidinyl; or R2 and R3, together with the nitrogen to which they are attached, form a morpholinyl ring;
R4 is C1-C4 alkyl; and R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C1-C6 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
R2 is selected from hydrogen or C1-C4 alkyl;
R3 is selected from C1-C4 alkyl, C3-C10 alkenyl, C5-C6 cycloalkylC1-C4 6 alkyl, C1-C6 alkoxycarbonylC1-C4 alkyl, C1-C6 alkylthio, heteroarylC1-C4 alkyl, or unsubstituted or substituted C7-C10 aralkyl wherein the substituent on the aralkyl are one or two substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl and unsubstituted or substituted C1-C4 alkoxy wherein the substituents on the alkoxy are one or two substituents independently selected from amino, C1-C4 alkylamino, C1-C4 dialkylamino, pyrrolidinyl, or piperidinyl; or R2 and R3, together with the nitrogen to which they are attached, form a morpholinyl ring;
R4 is C1-C4 alkyl; and R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C1-C6 alkylcarbonyl, or diphenylphosphinyl;
and pharmaceutically acceptable salts and prodrugs thereof.
22. The compound of Claim 20 of the formula wherein R1 is hydrogen or C1-C4 alkyl;
R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl; and R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl;
and pharmaceutically acceptable salts and prodrugs thereof.
R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, aryl or C7-C10 aralkyl; and R4 is C1-C6 alkyl, aryl, or C7-C10 aralkyl;
and pharmaceutically acceptable salts and prodrugs thereof.
23. A compound of Claim 22 which is 5,8-dihydroxy-traps-2-di(N
propylamino)-3-methyl-1,2,3,4-tetrahydronaphthalene and pharmaceutically acceptable salts and prodrugs thereof.
propylamino)-3-methyl-1,2,3,4-tetrahydronaphthalene and pharmaceutically acceptable salts and prodrugs thereof.
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 20.
25. A pharmaceutical composition made by mixing a compound of Claim 20 and a pharmaceutically acceptable carrier.
26. A process for making a pharmaceutical composition comprising mixing a compound of Claim 20 and a pharmaceutically acceptable carrier.
27. A method for diagnosing Alzheimer's disease, monitoring the progression and prognosis of Alzheimers disease and/or monitoring the therapeutic efficacy of any intervention or treatment of Alzheimer's disease comprising:
(a) obtaining a test sample from a subject wherein the test sample comprises circulating blood cells and/or olfactory neuroepithelial neuronal cell bodies or their neuronal processes; and (b) analyzing the test sample for interaction of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
(a) obtaining a test sample from a subject wherein the test sample comprises circulating blood cells and/or olfactory neuroepithelial neuronal cell bodies or their neuronal processes; and (b) analyzing the test sample for interaction of an amyloid beta peptide with alpha-7 nicotinic acetylcholine receptors.
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PCT/US1999/011702 WO1999062505A2 (en) | 1998-06-01 | 1999-05-27 | Method for treating neurodegenerative disorders |
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WO1999062505A3 (en) | 2000-04-06 |
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US20020013374A1 (en) | 2002-01-31 |
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