MXPA00011847A - Method for treating neurodegenerative disorders - Google Patents

Abstract

The invention is directed to 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 interaction of amyloid-beta with alpha-7 nicotinic acetylcholine receptors.

Description

METHOD FOR TREATING NEURODEGENERATIVE DISORDERS INTERREFERENCE WITH RELATED REQUEST This application claims priority of the provisional application of the United States Serial No. 60 / 087,577, filed June 1, 1998, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION The present invention provides a method for the treatment of neurodegenerative disorders. More particularly, a method for the treatment of neurodegenerative disorders (e.g.

Alzheimer's) by inhibiting the interaction of beta amyloid with the nicotinic acetylcholine alpha-7 receptors.

BACKGROUND OF THE INVENTION Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) afflict humanity with great suffering and financial loss. AD is characterized by neurofibrillary tangles, neuritic plaques and neuronal cell death. The AD appears well as the family form, of early onset (<60 years), or the late onset form (> 60 years), the latter being the most predominant. AD is the leading cause of age-related dementia and cognitive decline (Wisniewski T, Ghiso J., Frangione B., Neurobiol. Of Disease 1997, 4, 313-328). The amyloidogenic precursor protein (APP), the amyloid- or (A? -4o), and the -amyloid? -2 (A 1-42) are deeply implicated in the pathology of AD. Peptides A are derived from the APP by proteolytic processing. Dramatic evidence implicating peptides A, particularly A? -42, in AD, comes from several recently identified mutations that explain certain types of inherited AD. Such mutations in the presenilin genes (PS1 and PS2) are probably the cause of the most frequent form of early-onset familial AD (Rogaev E. Molecular Biology 1998, 32, 58). In these cases, as with APP mutations, more A? _42 is observed than A 1.40. Extensive studies have shown that Aβ-42 has a greater capacity than A 1.40 to aggregate into the amyloid fibrils that make up the AD characteristic plaques (Lansbury P.T. Jr. Accts, Chem. Res. 1996, 29, 317). Although A 1.40 is generally present to a much greater degree than A -? - 42 in the cerebrospinal fluid, it is A? _42 the major A-peptide found in AD plates. Peptides A can inhibit cholinergic neurotransmitter function independent of neurotoxicity (Auld D.S., Kar S., Quirion R., Trends Neurosci, 1988, 21 43). Peptides A bind to several natural substances such as apoE3, apoE4, apoJ, transthyretin and albumin. In addition, A has been reported to interact with a membrane bound receptor for advanced glycation end products and with the purifying receptor (SR) class A associated with the production of reactive oxygen species. The stimulation of the alpha-7 subtype of nicotinic acetylcholine receptors (nAChRs) can protect neurons against the cytotoxicity of A (Kihara T., et al., Ann Neurol, 1997, 42, 159). Also, it has been found that a number of compounds that activate nAChRs, especially of the alpha-7 subtype, have in vivo activity in cognitive enhancement models (U.S. Patent No. 5,741, 802, issued April 21, 1998). The specific binding of A 1.40 and A? -42 with alpha-7 subtype of nAChRs is described below. This new finding has wide ramifications for the etiology and treatment of AD. The nAChRs are members of the ligand input ion channel family, and appear to be formed of five protein subunits associated with each other around a central pore (Lindstrom J., Molecular Neurobiology 1997, 15, 193). These subunits include 1-9, 1-4,?,, And. Subtype 7 forms functional homomers that bind to -bungarotoxin, a peptide of 75 amino acids, with high affinity (Kd 0.65-1.7 nM), and nicotine with relatively low affinity (K <j approximately micromolar) (Holladay M.W., Dart M.J., Lynch J.K., J. Med. Chem. 1997, 40, 4169). Compounds that block the aggregation of peptides A are potentially useful drugs for the treatment of AD. For example, rifampicin inhibits aggregation of A and neurotoxicity, and may show an effect in vivo by decreasing plaque burden when compared to controls of the same age (Tomiyama T. et al., J. Biol. Chem. 1996, 271, 6839). To block the interaction of peptides A with nAChRs 7, compounds can be found that bind to nAChRs 7, A itself, or both. It would be expected that any of these mechanisms of action will produce significant protection against A-mediated neurotoxicity, and inhibition of cholinergic functioning mediated by nAChRs, and be very useful for the treatment of AD. The binding of A? -42 to the alpha-7 nAChRs produces a seed for the crystallization or deposition of A in insoluble deposits, which have the potential to grow in the fibrillar amyloid deposits characteristic of AD. Therefore, blocking the interaction of A? _42 with nAChRs alpha-7, should reduce the amount of aggregated insoluble A formed, and thus prevent the neurotoxicity and pathology associated with said aggregated amyloid deposits. Accordingly, an object of the invention is to provide a method for treating neurodegenerative disorders, by inhibiting the binding of amyloid beta peptides to the nicotinic acetylcholine alpha-7 receptors. A further object of the invention is to provide a method for the treatment of Alzheimer's disease, and / or to slow the progression of Alzheimer's disease, by inhibiting the binding of amyloid beta peptides to the nicotinic acetylcholine alpha-7 receptors. Another object of the invention is to provide a prediction method, a diagnostic method, a method for monitoring the prognosis, a method for monitoring progress, and a method for l i &d monitor the therapeutic efficacy of any therapeutic intervention used in Alzheimer's disease. Another object of the invention is to provide a method for identifying compounds that inhibit the binding of peptides A with nAChRs 7, by binding to peptides A or nAChRs 7.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to a method of treating a neurodegenerative disorder in a subject (preferably a human) in need thereof, comprising administering to the subject an amount of a compound effective to inhibit the binding of an amyloid beta peptide, preferably A ? -2, to the alpha-7 nAChRs, preferably human alpha-7 nAChRs. Since the nAChRs alpha-8 and alpha-9 are similar with respect to structure and function to the nAChRs alpha-7, it is possible that by blocking the interaction of -amyloid with the nAChRs alpha-8 and nAChRs alpha-9, we would also have a therapeutic effect. Neurodegenerative disorders included within the methods of the present invention include, without limitation, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (syndrome). of Shy-Drager), neuronal motor diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson complex- Guam dementia, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, degeneration striatonigral, Machado-Joseph disease / type 3 spinocerebellar ataxia and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal muscular atrophy and spinobulbar (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Ho ffman, Kugelberg-Weiander disease, Tay-Sach disease, Sandhoff's disease, familial spastic disease, Wohlfart-Kugelberg-Weiander disease, spastic paraparesis, progressive multifocal leukoencephalopathy and prion-related diseases (including Creutzfeldt-Jakob disease and Gerstmann-Stráussler-Scheinker, Kuru, and fatal familial insomnia). Other conditions also included within the methods of the present invention include dementia associated with age and other dementias and conditions with memory loss, including vascular dementia, diffuse gray matter disease (Binswanger's disease), dementia of endocrine or metabolic origin , dementia of head trauma and diffuse brain damage, pugilistic dementia and frontal lobe dementia. Also, other neurodegenerative disorders that originate from ischemia and cerebral infarction, including embolic occlusion and thrombotic occlusion, as well as intracranial hemorrhage of any type (including, without limitation, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral lesions ( including, without limitation, contusion, penetration, cutting, compression and laceration). Preferably, the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Tourette's syndrome, 5 amyotrophic lateral sclerosis, memory loss associated with age, senility and dementia associated with age, preferably, the neurodegenerative disorder is the Alzheimer disease. Because, preferably, the neurodegenerative disorder is Alzheimer's disease, also defined as an amyloidosis, other conditions within the methods of the present invention include other amyloidosis that share characteristic features including, without limitation, hereditary cerebral angiopathy, amyloid Non-neuropathic hereditary syndrome, Down syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-5 related amyloidosis, arthropathy of chronic hemodialysis and Finnish and Iowa amyloidosis. One embodiment of the invention is a method of treating and / or preventing dementia in an Alzheimer's patient (as well as a method of treating and / or preventing other clinical manifestations of Alzheimer's disease, including, without limitation, cognitive deficits. and language, apraxia, depression, disappointment and other neuropsychiatric symptoms and signs, and movement and gait abnormalities), which comprises administering to the subject a therapeutically effective amount of a íd,? *? xJ. . i, »> .t **, *. *. * .. -. . ., "». . , «" «. - .. .. . . . ¡¡A «¡» »Safc ^ < compound for inhibiting the binding of an amyloid beta peptide (preferably A? _42) with nAChRs, preferably nAChRs alpha-7, preferably human nAChRs alpha-7. The second embodiment of the invention is a method of improving the memory and / or mental state and / or stopping the progress of mental deterioration, in a patient with Alzheimer's disease, which comprises administering to the subject a therapeutically effective amount of a compound to inhibit the binding of an amyloid beta peptide (preferably A? -42) with nAChRs, preferably nAChRs alpha-7, preferably human alpha-7 nAChRs. Preferably, the compound used in the methods of treating neurodegenerative disorders, treating and / or preventing Alzheimer's disease and improving memory and / or stopping the progression of mental deterioration in a patient with Alzheimer's disease, is not estrogen , raloxifene, droloxifene, tamoxifen, idoxifen or levomeloxifene; preferably, the compound is not estrogen or a selective estrogen receptor modulator (SERM). A SERM is an estrogen receptor ligand that exhibits estrogen agonist activity in the cardiovascular system, CNS and bone, and estrogen antagonist activity in reproductive tissues such as the breast and uterus. Also included in the invention is the use of a compound that inhibits the binding of an amyloid beta peptide (preferably A? -42) to a nAChR alpha-7 (preferably a human alpha-7 nAChR) in the preparation of a medicament for the treatment of a neurodegenerative disorder in a subject (preferably human) in need thereof.

Another illustration of the invention is the use of a compound that inhibits the binding of an amyloid beta peptide (preferably A 1.42) to the nAChRs alpha-7 (preferably human nAChRs alpha-7), in the preparation of a medicament for: (a) improving memory; (b) stop the advance of mental deterioration observed in patients with Alzheimer's disease, (c) treat dementia, (d) prevent dementia in an Alzheimer's patient, and (e) treat and / or prevent other manifestations of the Alzheimer's disease including, without limitation, cognitive and language deficits, apraxia, depression, disillusions and other neuropsychiatric symptoms and signs, and movement and gait abnormalities in an Alzheimer's patient. Another aspect of the invention is a compound of formula I: I wherein R1 is hydrogen or CrC alkyl; R2 is selected from hydrogen, Ci-Cß alkyl, aryl or aralkyl of C -C? o; R3 is selected from hydrogen, Ci-Cß alkyl, C3-C-io alkenyl, C3-C8 cycloalkyl Ci-Cß alkyl, Ci-Cß alkoxycarbonyl Ci-Cß alkyl, Ci-Cß alkylthio, heteroaryl-C1-C4 alkyl, unsubstituted or substituted aryl or C7-C? or unsubstituted or substituted aralkyl, wherein the substituent on the aryl or aralkyl is one or more substituents independently selected from the group consisting of halogen, hydroxy , C -Cß alkyl and unsubstituted or substituted Ci-Cβ alkoxy, wherein the substituents on the alkoxy are one or more substituents independently selected from amino, Ci-Cß alkylamino, C6-cycloalkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six member heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; R 4 is C 6 alkyl, aryl, or C 7 -C aralkyl; and R5 and Re are each independently selected from hydrogen, C 1 -C 2 alkyl, C 3 -C 10 alkenyl, Ci-Cs alkylcarbonyl, or diphenylphosphinyl; and pharmaceutically acceptable salts and prodrugs thereof. In the preferred compounds of formula I, R1 is hydrogen; R2 is selected from hydrogen or C1-C4 alkyl; R3 is selected from C1-C4 alkyl, C3-C10 alkenyl, C5-C6 cycloalkyl-CrC4 alkyl, C6-C6 alkoxycarbonyl-C-alkyl C, Ci-Cβ alkylthio, heteroaryl-C- [alpha] -C4 alkyl, or unsubstituted or substituted C7-C- [alpha] 0- aralkyl, wherein the substituent on aralkyl is one or two substituents independently selected from the group consisting of of halogen, hydroxy, C 1 -C 4 alkyl and unsubstituted or substituted C 1 -C 4 alkoxy, wherein the substituents on the alkoxy are one or two substituents independently selected from amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino , pyrrolidinyl or piperidinyl; or R2 and R3. together with the nitrogen to which they are attached, they form a morpholinyl ring; R 4 is C 1 -C 4 alkyl; and R5 and Re are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C-i-C alqu alkylcarbonyl, or diphenylphosphinyl. A subclass of compounds of formula I has the formula: wherein R1 is hydrogen or C1-C4 alkyl; R2 and R3 are each independently selected from hydrogen, C, -C5 alkyl, aryl or C7-C6alkyl; and R 4 is C 7 -C 6 alkyl, aryl or C 7 -C aralkyl; and pharmaceutically acceptable salts thereof. The compounds of formula I are novel compounds that block the interaction of beta-amyloid with nAChRs alpha-7. Plus ^^^, - ^^^ g ^^^^ specifically, the compounds of formula I inhibit the binding of A 1.42 with human alpha-7 nAChRs, joining A-1-2. The orientation between the nitrogen atom and R4 about the appropriate ring can be either cis or trans. Preferably, the compound is 5,8-dihydroxy-trans-2-d, - (/ V-propyllamine) -3-methyl-1, 2,3,4-tetrahydronaphthalene, and its pharmaceutically acceptable salts. Other compounds useful in the methods of the present invention inhibit binding of A 1.42 with human alpha-7 nAChRs by directly binding to human alpha-7 nAChRs. An example of such compounds that bind to human alpha-7 nAChRs is bungarotoxin.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods of treating neurodegenerative disorders by inhibiting the binding of beta amyloid peptides to nAChRs alpha-7. Neurodegenerative disorders included within the methods of the present invention include, without limitation, Alzheimer's disease, Pick's disease, Lewi's diffuse body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (syndrome). of Shy-Drager), neuronal motor diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson-Guam Dementia complex, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, degeneration striatonigral, Machado-Joseph disease / type 3 spinocerebellar ataxia and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal muscular atrophy and spinobulbar (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Ho ffman, Kugelberg-Weiander disease, Tay-Sach disease, Sandhoff's disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy and prion-related diseases (including Creutzfeldt-Jakob disease and Gerstmann-Stráussler-Scheinker, Kuru, and fatal familial insomnia). Other conditions also included within the methods of the present invention include dementia associated with age and other dementias and conditions with memory loss, including vascular dementia, diffuse gray matter disease (Binswanger's disease), dementia of endocrine or metabolic origin , dementia of head trauma and diffuse brain damage, pugilistic dementia and frontal lobe dementia. Also, other neurodegenerative disorders that originate from ischemia and cerebral infarction, including embolic occlusion and thrombotic occlusion, as well as intracranial hemorrhage of any type (including, without limitation, epidural, subdural, subarachnoid and intracerebral), and intracranial and intravertebral lesions (including, without limitation, contusion, penetration, cutting, compression and laceration). Preferably, the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Tourette's syndrome, amyotrophic lateral sclerosis, memory loss associated with age, senility and dementia associated with age, preferably, the neurodegenerative disorder is the disease of Alzheimer's Because, preferably, the neurodegenerative disorder is Alzheimer's disease, also defined as an amyloidosis, other conditions within the methods of the present invention include other amyloidoses that share characteristic features including, without limitation, hereditary cerebral angiopathy, hereditary amyloid non-neuropathic, Down syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis arthropathy and Finnish and Iowa amyloidosis. The terms "beta amyloid", "amyloid beta peptide" or "beta-amyloid" as used herein, refer to beta amyloid peptides and include peptides A 1-40, A 1.42 and A 1.43, and their fragments. Examples of amyloid beta peptide fragments that have been shown to have biological activity and that are useful in the methods of the present invention, include, without limitation, fragment 1-28 and fragment 25-35 (eg, Yatin SM, Aksenov M ., Butterfield DA, Neurochem Res. 1999 Mar; 24 (3): 427-35; Hirakura Y., Satoh Y., Hirashima N., Suzuki T., Kagan B.L., Kirino Y., Biochem. Mol. Biol. Int. 1988, Nov; 46 (4): 787-94; Mazziotti M., Perlmutter D.H., Biochem. J. 1998 Jun 1; 332 (pt2): 517-24; Perovic S., Bohm M., Meesters E., Meinhardt A., Pergande G., Muller W.E., Mech Ageing Dev 1998 Mar 16; 101 (1-2): 1-19; Muller W.E., Eckert G.P., Scheuer K., Cairns N.J., Maras A., Gattaz W.F., Amyloid 1998 Mar; 5 (1): 10-5; Butterfield D.A., Martin L., Carney J.M., Hensley K., Life Sci. 1996; 58 (3): 217-28; Forloni G., Lucca E., Angeretti N., Della Torre P., Salmona M., J. Neurochem. 1997 Nov; 69 (5): 2048-54; Heese K., Hock C, Otten U., J. Neurochem. 1998 Feb: 70 (2): 699-707; Blanchard B.J., Konopka G., Russell N., Ingram V.M., Brain Res. 1997 Nov. 21; 776 (1-2): 40-50; Wu A., Derrico C.A., Hatem L, Colvin R.A., Neuroscience 1997 Oct; 80 (3): 675-84; Muller W.E., Romero F.J., Perovic S., Pergande G., Pialoglou P., J. Neurochem. 1997 Jun; 68 (6): 2371-7; Suh Y.H., J. Neurochem. 1997 May; 68 (5): 1781-91; Parpura-Gill A., Beitz D., Uemera E., Brain Res. 1997 Apr 18; 754 (1-2): 65-71; Fletcher T.G., Keire D.A., Protein Sci., 1997 Mar; 6 (3): 666-75; Scorziello A., Meucci O., Calvani M., Schettini G., Neurochem. Res. 1997 Mar; 22 (3): 257-65; Miguel-Hidalgo J.J., Vecino B., Fernandez-Novoa L., Alvarez A., Cacabelos R., Eur. Neuropsychopharmacol. 1998 Aug: 8 (3): 203-8; Maneiro E., Lombardi V.R., Lagares R., Cacabelos R., Methods Find Exp. Clin. Pharmacol. 1997 Jan-Feb; 19 (1): 5-12).

The term "subject" as used herein, refers to an animal, preferably a mammal, preferably a human being, who has been the object of treatment, observation or experimentation. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that produces the biological or medicinal response in a tissue, animal or human system, which is sought by a researcher, veterinarian, medical doctor. or another clinician, which includes alleviating the symptoms of the disease or disorder being treated. The term "alkyl" means straight or branched chain alkanes of one to ten carbons, or any number within this range. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2- methyl-butyl, neopentyl, n-hexyl, 2-hexyl and 2-methyl-pentyl. Alkoxy radicals are oxygen ethers formed from the aforementioned straight or branched chain alkyl groups. The cycloalkyl groups contain from 3 to 8 ring carbons, preferably from 5 to 7 carbons. Likewise, the alkenyl and alkynyl groups include straight or branched chain alkenes and alkynes having from 2 to 10 carbon atoms, or any number within this range. The term "aryl" denotes aromatic groups such as phenyl and naphthyl.

The term "C 7 -C aralkyl" or "means an alkyl group substituted with an aryl group in which the total number of carbon atoms is between 7 and 10 (for example, benzyl, phenylethyl, phenylpropyl). The term "heteroaryl" as used herein means a stable, unsubstituted or substituted, five- or six-membered monocyclic aromatic ring system, or a nine- or ten-membered benzo-fused heteroaromatic ring system, unsubstituted or substituted, consisting of of carbon atoms and one to four heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroaryl group may be attached to any hetero atom or carbon atom to result in the formation of a stable structure. Examples of heteroaryl groups include, without limitation, pyridyl, pyridazinyl, thienyl, furanyl, imida2: olyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl., benzothienyl, benzoisoxazolyl, benzooxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl or quinolinyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, thiadiazolyl, pyrazolyl, thienyl, triazolyl and quinolinyl. The term "N (CH2) 5" means a piperidinyl group. The term "cCßHn" refers to a cyclohexyl group. When a particular group is "substituted" (eg, aryl, aralkyl), that group may have one or more substituents, preferably one to five substituents, preferably one to three substituents, and one to two substituents is very preferred. , selected independently from the list of substituents. Under the standard nomenclature used throughout this description, the terminal portion of the designated side chain is first described, followed by functionality adjacent to the point of attachment. Thus, for example, a "phenyl-alkylamido substituent of CrC6-Ci-Cß alkyl" refers to a group of the formula: Compounds that are useful in the methods of the present invention to inhibit the interaction between Aβ-40 and Aβ42 and the alpha-7 subtype of nAChRs, for the purpose of direct therapeutic intervention, or to select compounds that act by this mechanism includes compounds of formula I, especially 5,8-dihydroxy-trans-2-di- (? / - propylamino) -3-methyl-1, 2,3,4-tetrahydronaphthalene (compound 9), ( -) - nicotine, (rac) -epibatidine, bungarotoxin, and pharmaceutically acceptable salts thereof. Certain extensions of human nAChR alpha-7 peptide bind to amyloid beta, and can be used in place of nAChR alpha-7 along with beta amyloid in order to select collections to find compounds that block the interaction between beta amyloid and nAChR human alpha-7. Included among these peptide extensions of the human alia-7 nAChR, is the nAChRI peptide 93-224 alpha-7, and smaller peptides derived from the same, as indicated in the following table.

PICTURE Compound Improvement of A -42 mediated inhibition of ACh release in rat cortical synaptosomes (%) nAChRI 93-224 81% at 10 m alpha-7 human 79% at 1 m AC-NGEWDLVGIPGKRSERFYECCKEPYPDVTFTV-NH2 nAChR200-214 79% at 10 m alpha-7 human 71% at 1 m AC-GIPGKRSERFYECCK-NH2 nAChR206-216 81% at 10 m alpha-7 human 77% at 1 m AC-SERFYECCKEP-NH2 nAChR206-216 84% at 10 m alpha-7 human 82% at 1 m oxidized (cyclic) CC: Ac-SERFYECCKEP-NH2 nAChR206-216 22% at 10 m alpha-7 human 10% at 1 m SERFYECCKEP nAChR210-213 72% at 10 m alpha-7 human 59% at 1 m AC-YECC-NH2 The one-letter standard code for amino acids has been used for the compounds. This code is listed in Lehninger A.I., "Biochemistry" -biochemistry- second edition, Worth Publishers Inc., New York, 1976, pages 73-75. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be useful in the preparation of the compounds according to this invention, or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid , succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds of the invention carry an acidic portion, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, for example sodium or potassium salts; alkaline earth metal salts, for example calcium or magnesium salts; and salts formed with suitable organic ligands, for example quaternary ammonium salts. The present invention includes within its scope prodrugs of the compounds of the invention. A prodrug is inactive as administered, but is activated in vivo. The prodrug is converted to the original drug either chemically or by specific enzymes. Higuchi T., Stella V., eds. "Pro-Drugs as Novel Drug Delivery Systems" -Pharmaceuticals as novel drug delivery systems-, American Chemical Society, Washington DC, 1976. In general, said prodrugs will be functional derivatives of compounds that are readily convertible in vivo into the compound required. Thus, in the methods of treatment of the present invention, the term "administer" should encompass the treatment of the various disorders described, with the specifically mentioned compound, or with a compound that may not be specifically mentioned, but which becomes in vivo in the specified compound after its administration to the patient. The conventional procedures for the selection and preparation of suitable derivatized prodrugs, are described for example in "Design of Prodrugs" -Prodrug Design-, ed. H. Bundgaard, Elsevier, 1985. When the compounds according to this invention have at least one chiral center, they can therefore exist as enantiomers. When the compounds have two or more chiral centers, they can also exist as diastereomers. It should be understood that such isomers and mixtures thereof are encompassed within the scope of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs and these are considered to be included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or with common organic solvents, and said solvates are also considered to be encompassed within the scope of this invention.

The (-) - nicotine is (-) - 1-methyl-2- (3-pyridinyl) pyrrolidone, and is readily available from Sigma Chemical Company.

(-)-Nicotine The (+/-) - epibatidine is exo - (+/-) - 2- (6-chloro-3-pyridinyl) -7-azabicyclo [2.2.1] heptane, and is readily available from Sigma Chemical Company. (rae) Epibatidine The -bungarotoxin is a peptide of 74 amino acids that is commercially available from Research Biochemicals Inc .. The bungarotoxin and its amino acid sequence are described in Lee C.Y., Annu. Rev. Pharmacol., 1972, 12, 265-281. Peptides 125 I-A 1-40, fluo-A-O and anti-nAChR alpha-7 antibodies are commercially available from Amersham Pharmacia Biotech, Advanced Bioconcepts and Research Biochemical International, respectively. 125 I -bungarotoxin is commercially available from Amersham Pharmacia Biotech. The present invention therefore provides a method of treating a neurodegenerative disorder, comprising administering any of the compounds defined herein in an amount effective to treat the neurodegenerative disorder. Preferably, the compound is not estrogen, raloxifene, droliphene, tamoxifen, idoxifen or levomeloxifene; preferably, the compound is not estrogen or a selective estrogen receptor modulator (SERM): The compound can be administered to a patient suffering from a neurodegenerative disorder, by any conventional route of administration, including, without limitation, intravenously, oral, subcutaneous, intramuscular, intradermal, buccal, intracerebral and other parenteral routes. The amount of the compound that is effective to treat a neurodegenerative disorder is between 0.01 mg per kg and 10 mg per kg of body weight of the subject. The method of treatment of the neurodegenerative disorders described in the present invention can also be carried out using a pharmaceutical composition containing any of the compounds defined herein, and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain about 0.5 mg to 200 mg of the compound, and may be constituted in any suitable form for the selected mode of administration. The carriers include necessary and inert pharmaceutical excipients including, without limitation, binders, suspending agents, lubricants, flavors, sweeteners, preservatives, dyes and coatings. Compositions suitable for oral administration include solid forms such as pills, capsules, granules, tablets, caplets and powders; and liquid forms such as solutions, syrups, elixirs and suspensions. Useful forms for the intracerebral and other parenteral routes of administration include saline solutions, emulsions and suspensions. Optimal dosages to be administered can be readily determined by the person skilled in the art, and have to vary with the particular compound used, the mode of administration, the concentration of the preparation, and the progress of the pathological condition. In addition, due to the factors associated with the particular patient to be treated, which include the patient's age, body weight, diet, physical activity and time of administration, and associated morbidities and clinical conditions, there will be a need to adjust the dosages . The present invention also provides useful diagnostic tools for diagnosing Alzheimer's disease. Alzheimer's disease (AD) exhibits neuropathological abnormalities in the olfactory system located in the nasal cavity. These include the presence of dystrophic neurites that exhibit tau immunoreactivity, neurofilaments, apolipoprotein E and other proteins, abnormal tau protein, increased superoxide dismutase, and beta-amyloid deposition in the primary sensory cells (olfactory receptor) and nerve fibers of the tissue of the nasal mucosa (Arnold et al., Ann. NY Acad. Sci., 1998, Nov. 30; 855: 762-75; Hock et al., Eur. Neurol. 1998 Jul: 40 (1): 31-6; Johnson and others, Neurobiol. Aging 1994 Nov-Dec; 15 (6): 675-80; Kulkarni-Narla et al., Exp. Neurol. 1996 Aug; 140 (2): 115-25; Lee and others, Exp. Neurol. 1993, May; 121 (1): 93-105; Tabaton et al., Neurology 1991 Mar; 41 (3): 391-4; Tálamo and others, Ann N.Y. Acad. Sci. 1991; 640: 1-7; Yamagishi and others, Ann. Otol. Rhinol Laryngol. 1998 May; 107 (5Pt1): 421-6; Yamagishi and others, Nippon Jibiinkoka Gakki Kaiho 1994 Jan; 97 (1): 51-60). These observations recapitulate the neuropathological profile and neurodegenerative abnormalities (eg, cytoskeletal changes, protein immunoreactivity and beta-amyloid deposition) observed in neurons of the central nervous system of AD patients. Routine access to these fibers and sensory neurons can be performed with nasal biopsy in AD patients (eg, Feron et al., Arch. Otolaryngol, Head Neck Surg, 1998 Aug; 124 (8): 861-6). Olfactory neuroblasts (olfactory neurons obtained by biopsy and placed in primary cell culture) of AD patients produce carboxy terminal fragments of the precursor amyloidogenic protein (APP) containing beta-amyloid (A-beta, Crino et al., Ann.Otol. Rhinol, Laryngol, 1995, Aug; 104 (8): 655-61). Crino and others showed A-beta labeling in the basal third of the olfactory neuroepithelium and in axons that project through the lamina of AD patients. Thioflavin-S staining that detects amyloid deposition in the basal third of the olfactory neuroepithelium of AD patients was also observed. Nicotinic acetylcholine alpha-7 receptors are present in olfactory neurons, probably including olfactory receptor cells in the nasal cavity (Alkondon et al., Neurosci.Lett 1994, Aug. 1; 176 (2): 152-6; Alkondon et al., Eur. J. Neurosci., 1997, Dec. 9 (12): 2734-42, Bouvet et al., Neurosci Res. 1988 Feb; 5 (3): 214-23; Edwards et al., Experientia 1987 Aug15; 43 (8) : 868-73; Edwards et al., Experientia 1988 Mar 15; 44 (3): 208-11; Seguela et al., J. Neurosci. 1993 Feb; 13 (2): 596-604). Beta-amyloid peptide increases free cytosolic Ca2 + in AD lymphoblasts (I Jimmy and others, Alzheimer Dis. Assoc. Disord 1997 Dec. 11 (4): 220-7), and raises mitogen-induced Ca2 + responses in freshly prepared human lymphocytes (Eckert et al., Life Sci. 1994: 55 (25-26): 2019-29). The precursor amyloidogenic protein (APP) can be induced on the cell surface of human lymphocytes after stimulation (Bullido et al., Biochim, Biophys, Acta 1996 Aug 21; 1313 (1): 54-62) and there is an increase in the APP isoform. -770 in lymphocytes from AD patients (Ebstein et al., Brain Res. Mol. Brain Res. 1996 Jan; 35 (1-2): 260-8). Lymphoblastoid cells from patients with familial AD of early onset and late onset show increased expression of mRNA and beta-APP protein (Matsumoto et al., Eur. J. Biochem., 1993, Oct. 1; 217 (1): 21-7). Lymphocytes from AD patients also exhibit increased level of mRNA for the nicotinic 7-alpha receptor (Hellstrom-Lindahl et al., Brain Res. Mol. Brain Res. 1999 Mar 20; 66 (1-2): 94-103).

Based on the aforementioned information, the authors of the present invention propose that the analysis of the nicotinic receptor interaction of acetylcholine alpha 7-beta amyloid peptides, in the cells circulating in the blood and in neurons / olfactory neuroepithelial neuronal processes, or olfactory neuroblasts, obtained from AD patients, can be used as diagnostic tools, markers of AD progression and prognosis, and markers of therapeutic efficacy for any intervention or treatment directed against AD. In this manner, the present invention provides methods to diagnose Alzheimer's disease, monitor the progress and prognosis of Alzheimer's disease and / or monitor 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 cells circulating in the blood and / or olfactory neuroepithelial neuronal cell bodies or their neuronal extensions (i.e., dendrites and axons of a neuron); and (b) analyzing the test sample for the interaction of an amyloid beta peptide (including, without limitation, A? ^ 0, A? ^ 2 and A-3 and its fragments) with nicotinic acetylcholine-alpha receptors. 7 The compounds of formula I, such as 5,8-dihydroxy-raps-2-di - (? / - propylamino) -3-methyl-1, 2,3,4-tetrahydronaphthalene (compound 9) are prepared in accordance with procedures that are described in the schemes and examples that follow. The abbreviations used in the present specification, particularly in the schemes and examples, are as follows: Ac-acetyl Ach = acetylcholine AcOH = acetic acid BSA = bovine serum albumin DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide Et3N = triethylamine EtOAc = ethyl acetate FCS = fetal calf serum 15 i-Pr = isopropyl Me = methyl Mel = methyl iodide nAChR = nicotinic acetylcholine receptor Ph = phenyl 20 PCC = pyridinium chlorochromate TEA = triethylamine THF = tetrahydrofuran CCD = delta layer chromatography - SCHEME 1 (4) (5) (6) (7) (8) (9) The compounds of the invention can be prepared as shown in scheme 1. First a Diels-Alder reaction on benzophenone (1) is performed with a suitable diene such as isoprene, to give a dione as (2). Then, the base catalyzed isomerization of (2) produces a 1,4-dihydroxyphenyl compound (3), which is converted to the dimethyl ether (4). The hydroboration followed by oxidation gives the alcohol (5), which is then oxidized to the ketone (6). Reductive amination is then carried out with an amine such as propylamine, using a suitable hydride reducing agent such as sodium cyanoborohydride, to give the compound 7. This material can then be subjected to a reductive amination reaction such as for example with propionaldehyde, as shown, to produce (8). The compound (8) is then treated with HBr in acetic acid to decompose the methyl ethers and form the dihydroxy compound (9). Alternatively, BBr3 can be used to decompose the methyl ethers and form the dihydroxy compound (9). In addition, a deficit of BBr3 can be used to give compounds in which only one of the methyl ethers is removed to produce compounds with a hydroxy group and a methoxy group. (10) (11) (12) (1) SCHEME 2 An additional means of preparation of the compounds of the present invention is illustrated in Scheme 2. A suitable propargyl alcohol such as 3-hydroxy-3-methyl-1-butyne (10, R4 = Me), is dehydrated to give an enyne such as compound 11. This material is then subjected to an aminomercure reaction to produce a 2-amino-1,4-butadiene, such as compound (12). The Diels-Alder reaction of compound (12) with benzophenone (1) gives (13), which can be isomerized as in scheme 1 with a base, to give the compound 1,5-dihydroxy (14). The catalytic reduction of the double bond of (14) with hydrogen and palladium on carbon, such as palladium 10% on carbon, produces compounds of the invention such as (15). Compounds of type 9 can be treated with a base such as triethylamine in a suitable solvent such as dioxane or methylene chloride together with electrophiles, such as acid halides or alkyl halides, to give the substitution products on one or both hydroxyls phenolic Said compounds may be active on their own or serve as prodrugs for the compound 9. The following examples are described to aid the understanding of the invention, and are not intended, nor should be considered in any way, to be limiting of the invention. which is described in the claims that follow later.

EXAMPLE 1 Preparation of 5.8-dihydroxy-frans-2-di - (/ V-propylamino) -3-methyl-1, 2,3,4-tetrahydronaphthalene (9) (a) 5.8-Dihydroxy-2-methylene-1,4-dihydronaphthalene (3) To a solution of p-benzoquinone (10.00 g, 92.5 mmol) in 1 M solution of lithium perchlorate, in nitromethane (300 ml), He added isoprene (9.24 ml, 92.3 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature under N2 for 4 hours. The reaction mixture was partitioned between EtOAc (500 ml) and water (200 ml). The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 2 as a brown solid. The reaction was repeated on 15 g of benzoquinone to produce additional 2. The products of these two operations were combined and occupied later without further purification. To a solution of 2 (35.00 g, 199 mmol) in methylene chloride (400 ml), triethylamine (40 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The product was precipitated from the solution by the addition of hexane (300 ml). The solid was collected by filtration and dried overnight in a desiccator under high vacuum to give 3 as a light brown solid. 1 H NMR (300 MHz DMSO-d 6): 1.75 (s, 3 H), 3.00-3.01 (m, 2 H), 3.09 (s, 2 H), 5.53 (1 H s), 6.43 (s, 2 H), 8.49- 8.52 (m, 2H). ^^^^^ (b) 5,8-Dimethoxy-2-methyl-1,4-dihydronaphthalene (4) To a cold solution (-78 ° C) of hydroquinone 3 (17.00 g, 96.6 mmol) in DMF under N2, Sodium hydride was added without washing at 60% in mineral oil (8.90 g, 222.5 mmol). The resulting reaction mixture was warmed to room temperature over a period of 30 minutes and subsequently treated with methyl iodide (14.3 ml, 230 mmol). After stirring the reaction mixture for 1 hour at room temperature, the reaction mixture was diluted with ethyl acetate (1.5 L) and washed with brine (3 x 500 ml). The organic solution was dried over sodium sulfate, filtered, concentrated and the residue was purified on silica gel (elution with 20% ethyl acetate / hexane) to give 4 as a light yellow oil which solidified upon standing. 1 H NMR (300 MHz CD3OD): 1.77 (s, CH 3), 3.07-3.09 (m, 2 H), 3.16 (br s, 2 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 5.52-5.53 ( m, 1 H), 6.65 (s, 2H). (c) 5,8-Dimethoxy-.raps-2-hydroxy-3-methyl-1, 2,3,4-tetrahydronaphthalene A solution of 4 (5.00 g, 24.5 mmol) in tetrahydrofuran (100 mL) was cooled to 0 ° C and treated with 1 M borane-tetrahydrofuran complex (24.5 mL, 24.5 mmol) and the resulting solution was stirred at room temperature During 4 hours. Then, 12 ml of 3N NaOH solution was slowly added to the reaction mixture solution, followed by the addition of 6 ml of 30% aqueous hydrogen peroxide. After stirring for 30 minutes, the resulting mixture was diluted with 500 ml of ethyl acetate and washed with brine (2 x 100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated, and the residue was purified on silica gel (30% ethyl acetate / hexane) to give 5 as a white solid. 1 H NMR (300 MHz, CDCl 3): 1.13 (d, 3 H, J = 6.51 Hz), 1.60 (d, 1 H), 1.75-1.90 (m, 1 H), 2.26 (dd, 1H, J = 10.0 Hz, 17.57 Hz), 2.48 (dd, 1 H, J = 8.93, Hz, 17.10 Hz), 2.96 (dd, 1 H, J = 5.31, 17.7 Hz), 3.16 (dd, 1 H, J = 5.33, 5.35 Hz), 3.63-3.69 (m, 1 H), 3.78 (s, 6H), 6.62 (s, 2H). (d) 5,8-Dimethoxy-3-methyl-2-tetralone (6) A solution of alcohol 5 (10 g, 45 mmol) and dichloromethane (200 ml) at -30 ° C was treated dropwise with chloride of oxalyl (4.92 g, 24 ml, 0.275 moles). The reaction was stirred at -30 ° C for 30 minutes, cooled to -60 ° C and DMSO (6.4 ml) was slowly added over 15 minutes. The reaction was stirred for one hour, cooled to -78 ° C for 30 minutes, and then treated dropwise with triethylamine (40 ml). The reaction was warmed to room temperature and stirred for 1 hour, followed by the addition of water and dichloromethane with complete mixing. The organic layer was separated, dried with MgSO 4, filtered and the solvent was evaporated to leave an oil. Purification of this material using flash chromatography (vaporized silica, hexane / EtOAc: 70/30) yielded 6 as a white crystalline solid. 1 H NMR (300 MHz, CDCl 3) 6.7 (q, 2 H), 3.78 (s, 3 H), 3.75 (s, 3 H), 3.5 (dd, 2 H), 3.3 (m, 1 H), 2.55 (m, 2 H), 1.2 (d, 3 H). (e) 5.8-D-methoxy-2 -? / - propylamino-3-methyl-1.2.3.4-tetrahydronaphthalene I7 To a solution of 6 (0.15 g, 0.68 mmole) in acetonitrile (10 ml), cyanoborohydride was added. sodium (0.085 g, 1.30 mmol), 0.05 ml of acetic acid and? / - propylamine (0.08 ml, 1.3 mmol). The resulting solution was stirred at room temperature overnight and was poured into 10 ml of 1 N NaOH solution. The mixture was extracted with EtOAc, dried over sodium sulfate, concentrated, and the residue was purified by preparative CCD (elution with 30% ethyl acetate in hexane) to give the amine 7 as a colorless oil. 1 H NMR (300 MHz CD3OD): 0.85 (d, 3H, J = 7.07 Hz), 0.93-0.97 (m, 3H), 1.09 (t, 2H), 1.49-1.61 (m, 2H), 2.12-2.42 (m , 2H), 2.51-2.76 (m, 4H), 2.82-3.08 (m, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 6.65 (s, 2H). (f) 5, 8-D-methoxy-frans-2-di (/ V-propylamino) -3-methy1- 1.2.3.4-tetrahydronaphthalene (8) To a solution of 7 (0.11 g, 0.42 mmole) in acetonitrile (10 ml), sodium cyanoborohydride (0.05 g, 0.6 mmol), 0.03 ml acetic acid and propionaldehyde (0.045 ml, 0.60 mmol) were added. The resulting solution was stirred overnight at room temperature and was emptied into 10 ml of 1 N NaOH solution. The mixture was extracted with EtOAc, dried over sodium sulfate, concentrated, and the residue was purified by preparative CCD (elution with 30% ethyl acetate in hexane) to give the amine 8 as a light yellow solid. 1 H NMR (300 MHz CD3OD): 0.84 (d, 3H, J == 6.94 Hz), 0.92 (t, 2H, J = 7.30, 7.32Hz), 1.27-1.59 (m, 4H), 2.33-2.42 (m, 2H), 2.54-3.02 (m, 8H), 3.73 (s, 3H), 3.76 (s, 3H) , 6.66 (s, 2H). In a similar manner, compounds 19, 21, 25, 27, 29, 35, 37, 39, 41, 52 and 54 were prepared. To separate the enantiomers from 8, 2.859 g of 8 were passed through a chromatography column. High pressure liquids based on CHIRALPAKR AD ™ chiral cellulose (8 cm x 30 cm) at 25 ° C using hexane / isopropyl alcohol (99/1) as eluent to give two fractions as oils. Fraction 1 (18) had an enantiomeric excess (e.e.) of 98.6%, and fraction 2 (17) had an e.e. of 97.9%. Fraction 1 (0.306 g, 1.0 mmol) and fumaric acid (0.141 g, 1.2 mmol) in ethanol (2 ml) were dissolved with heating. The ethanol was evaporated and the residue was triturated with diethyl ether to produce the fumarate salt of 18 as a white solid. In the same way, the fumarate salt of 17 of fraction 2 (0.301 g, 1.0 mmol) and fumaric acid (0.141 g, 1.2 mmol) was obtained. (g) 5.8-Dihydroxy-.rans-2-di (? / - propylamino) -3-methyl-1.2.3.4-tetrahydronaphthalene (9) A mixture of 8 (1.4 g, 4.6 mmol) and 3.5 ml of aqueous HBr. 48% acetic acid (3.5 ml) was stirred at 100 ° C under N2 overnight. The reaction mixture was then cooled to 0 ° C and extracted with diethyl ether (20 ml). The organic solution was neutralized with aqueous NaHCOß and separated. The aqueous layer was extracted with ether (20 ml) and the combined ether solutions were dried over Na 2 SO 4, filtered and concentrated to give 9. 1 H NMR (600 MHz, CDCl 3): 0.86-0.92 (dt, 6H), 1.13 ( d, 3H, J = 6.42 Hz), 1.42-1.50 (m, 4H), 1.88-1.93 (m, 1 H), 2.23-2.28 (m, 1 H), 2.39-2.52 (m, 6H), 2.61-2.63 (m, 1 H), 2.90 (dd, 1H, J = 4.75, 16.28 Hz), 2.95 (dd, 1H, J = 5.05, 16.75Hz), 4.84 (br, s, 2H), 6.50 (dd, 2H, J = 8.52Hz). EM-CI: m / e MH + 278 (40%). Similarly, 17 and 18 were converted into 15 and 16, respectively. Additionally, the demethylation of the appropriate dimethyl ethers by the process described herein leads to the preparation of the compounds 20, 22, 26, 28, 30, 32, 34, 36, 40, 42, 53 and 55. In the course of the demethylation of 37, butyl ether was also removed to obtain 38.

EXAMPLE 2 Preparation of 5,8-dihydroxy-c / s-2- (1-morpholinyl) -3-methyl-1,2,3,4-tetrahydronaphthalene (24) (a) 5.8-Dimethoxy-c / s-2- (1-morpholinyl) -3-methyl-1.2.3.4-tetrahydro-naphthalene (23) Ketone 6 (0.299 g, 1.36 mmole) was dissolved in toluene (1 ml ) followed by the addition of morpholine (0.130 g, 0.13 ml, 1.5 mmol) and Ti (/ - PrO) 4 (0.611 g, 0.64 ml, 2.15 mmol). The reaction mixture was stirred for 15 hours at room temperature. Methanol (2 rnl) was added followed by the portionwise addition of NaBH 4 (0.15 g, 3.9 mmoles) for 1 hour. Dichloromethane and 1N NaOH were added with complete mixing; the organic layer was separated, dried with MgSO 4, filtered and evaporated to leave an oil. Purification of this material using flash chromatography (vaporized silica, hexane / EtOAc: 75/25) yielded 23. 1 H NMR (300 MHz DMSO-d 6): 6.6 (s, 2 H), 3.6 (d, 6 H), 3.5 (s, 4 H), 3.2 (s, 4 H), 3.2 (s, 6 H), 2.8 (d, 1 H), 2.7 (d, 1 H), 2.3 (rn, 2 H), 2.05 ( m, 2 H), 0.6 (d, 3 H). (b) 5.8-Dihydroxy-c / s-2- (1-morpholinyl) -3-methylene-1, 2.3.4-tetrahydro-naphthalene (24) A solution of 23 (20 mg, 0.066 mmol) and dichloromethane (2 ml) at -78 ° C, treated with a 1M solution of BBr3 in dichloromethane (1 ml, 1 mmol) and stirred for 1 hour at -78 ° C. After warming to room temperature, methanol (5 ml) was added and the solvents evaporated. The addition of methanol to the residue was done twice, followed by evaporation. The residue was dissolved in acetonitrile (25 ml) and treated with rietylamine (2 ml). After stirring for 2 hours, water and ethyl acetate were added with complete mixing. The organic layer was separated, dried with MgSO 4, filtered and the solvent was evaporated to yield 24 as an oil. 1 H NMR (300 MHz CD3OD): 6.7 (s, 2 H), 3.4 (m, 4 H), 3.3 (m, 1 H), 2.6 (m, 5 H), 1.9 (m, 1 H), 1.5 ( m, 2 H), 1.05 (d, 3 H), 0.9 (m, 3 H).

EXAMPLE 3 Preparation of 5,8-dimethoxy-c / s- and frans-2- (V-propyl-? -prOpargyl) amino-3-methyl-1,2,3,4-tetrahydronaphthalene (31 v 33) Ketone 6 (1 g, 4.5 mmol) was dissolved in acetonitrile (75 ml) followed by the addition of acetic acid (0.54 ml, 9 mmol, 2 equivalents) and propargylamine (0.6 ml, 9 mmol, 2 equivalents). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (0.6 g, 9 mmol, 2 equivalents) (3x) was added portionwise for 1.5 hours (every 30 minutes), and the reaction mixture was stirred overnight at room temperature. Ethyl acetate and 1 N NaOH were added with complete mixing and the organic layer was separated, dried with MgSO 4, filtered and evaporated to leave an oil. The product was purified by flash chromatography (ethyl acetate: hexane / 50:50) to yield a 5,8-dimethoxy-c / s- and / raps-2-α / - (propargyl) amino-3 oil. -methyl-1, 2,3,4-tetrahydronaphthalene (1.2 g, 100%). This material was dissolved in acetonitrile together with propionaldehyde (0.65 g, 9 mmol, 2 equivalents) and acetic acid (0.5 ml, 9 mmol) and stirred 1 hour at room temperature. One hour later, sodium cyanoborohydride (0.6 g, 9 mmol, 2 equivalents) (3x) was added portionwise for 1.5 hours (every 30 minutes). The reaction was stirred overnight at room temperature. Ethyl acetate and 1 N NaOH were added to the reaction with complete mixing and the organic layer was separated, dried with MgSO 4, filtered and evaporated to leave a mixture of products. and 33. Purification of this material using flash chromatography (vaporized silica, hexane: ether / 80: 20) yielded 31 and 33. Compound 31: 1 H NMR (300 MHz, CDCl 3) 6.6 (s, 2 H), 3.8 (s, 6 H), 3.4 (q, 2 H), 3.0 (dd, 2 H), 2.6 (m, 4 H), 2.2 (m, 2 H), 1.85 (m, 1 H), 1.5 (m , 2 H), 1.1 (d, 3 H), 0.9 (t, 3 H). Compound 33: 1 H NMR (300 MHz, CDCl 3) 6.6 (s, 2 H), 3.78 (s, 3 H), 3.75 (s, 3.H), 3.6 (q, 2 H), 3.05 (dd, 1 H ), 2.75 (m, 2 H), 2.61 (m, 3 H), 2.3 (m, 2 H), 2.1 (s, 1 H), 1.55 (m, 2 H), 0.9 (t, 3 H), 0.8 (d, 3 H).

EXAMPLE 4 Preparation of 5-r2- (3-methyl) butenin-8-hydroxy-frans-2-di (/ V-propylamino) -3-methyl-1.2.3.4-tetrahydronaphthalene (43): v 5 -hydroxy-8-r2- (3-methyl) butenip-frans-2-di (? -propylamino) -3-methyl-1,2,3,4-tetrahydronaphthalene (44) Diol 9 (0.3 g, 1.2 mmol) was dissolved in acetone (40 ml) followed by the addition of potassium carbonate (0.19 g) and 1-bromo-3-methyl-2-butene (0.1 ml, 0.87 mmol). The reaction mixture was stirred for 48 hours at room temperature. Dichloromethane and water were added with complete mixing and the organic layer was separated, dried with MgSO 4, filtered, and the solvent was evaporated to yield an oil. Purification of this material using flash chromatography (vaporized silica, hexane: ether / 70: 30) yielded 43 and 44. The regiochemical structural assignment between the two is uncertain. Compound 43: 1 H NMR (300 MHz, CDCl 3) 6.5 (s, 2 H), 5.5 (t, 1 H), 4.4 (m, 2 H), 3.0 (m, 2 H), 2.4 (m, 8 H), 1.8 (m, 1 H), 1.72 (s, 3 H), 1.65 (s, 3 H) ), 1.4 (m, 4 H), 1.1 (dd, 3 H), 0.85 (t, 6 H). Compound 44: 1 H NMR (300 MHz, CDCl 3) 6.55 (s, 2 H), 5.45 (t, 1 H), 4.4 (m, 2 H), 3.05 (dd, 1 H), 2.85 (dd, 1 H) , 2.4 (m, 7 H), 1.65 (s, 3 H), 1.6 (s, 3 H), 1.55 (m, 2 H), 1.4 (m, 4 H), 1.1 (m, 4 H), 1.1 (d, 3 H), 0.9 (t, 6 H).EXAMPLE 5 Preparation of 5-hydroxy-8-methoxy-frans-2-di (? / - propylamino) -3-methyl-1,2,3,4-tetrahydronaphthalene (45): v 5-methoxy-8-hydroxy-frans-2- di (? / - propylamino) -3-methyl-1.2.3.4-tetrahydronaphthaler? or (46) Compound 8 (1.85 g, 6 mmol) was dissolved in dichloromethane (20 ml) and cooled to -78 ° C, followed by the addition of boron tribromide (6 ml of a 1 M solution, 6 mmol, 1 equivalent). . The reaction mixture was stirred at -78 ° C for 1 hour and then warmed to room temperature for 2 hours. The reaction was quenched with methanol (5 ml) and the solvent was evaporated (the ethanol quenching was repeated twice more). The resulting oil was dried overnight at high vacuum (5 mm Hg). The residue was dissolved in dichloromethane and NaHCO 3 was added, mixed thoroughly and the organic layer was separated, dried with MgSO 4, filtered and the solvent was evaporated to leave a mixture of two regioisomers 45 and 46 (1: 1). Purification of a mixture (200 mg) was carried out in a reverse phase CLAP (column C18, water: acetonitrile: trifluoroacetic acid / 69: 30: 1) to produce 45 and 46 as trifluoroacetate salts. Compound 45 (TFA salt): 1 H NMR (300 MHz, CDCl 3) 6.65 (q, 2 H), 4.7 (bs, 1 H), 3.7 (s, 3 H), 3.5 (m, 1 H), 3.3 (m , 1 H), 3.0 (m, 4H), 2.7 (m, 2 H), 2.3 (m, 1 H), 2.0 (m, 5 H), 1.15 (d, 3 H), 0.9 (m, 6 H) ).

Compound 46 (free base): 1 H NMR (300 MHz, CDCl 3) 6.55 (q, 2 H), 4.3 (bs, 1 H), 3.75 (s, 3 H), 3.05 (dd, 1 H), 3.0 (dd) , 1 H), 2.6 (m, 1 H), 2.4 (m, 6 H), 2.2 (m, 1 H), 1.8 (m, 1 H), 1.4 (m, 4 H), 1.1 (d, 3 H) 0.85 (t, 6 H). The regiochemistry of the 46 structure was confirmed by careful analysis of HMBC (heteronuclear multiple link correlation) connectivity and nOe effects. The structure of 46 was established by connectivity between the methoxy substituent on the aromatic ring and the benzylic methylene adjacent to the methyl substituted carbon.

EXAMPLE 6 Preparation of 5,8-dimethoxy-2-r / v- (L-alanylmethyl ester) 1-3-methyl-1, 2.3.4-tetrahydronaphthalene (48) Ketone 6 (1 g, 4.5 mmol) was dissolved in acetonitrile (75 ml) and acetic acid (0.54 ml, 9 mmol, 2 equivalents) and alanine methyl ester hydrochloride (1.3 g, 9 mmol, 2 equivalents) were added. . The reaction was stirred at room temperature for 1 hour and then sodium cyanoborohydride (0.6 g, 9 mmol, 2 equivalents) (3x) was added portionwise (3x) for 1.5 hours (every 30 minutes). The reaction was stirred overnight at room temperature. Ethyl acetate and 1 N NaOH were added with complete mixing and the organic layer was separated, dried with MgSO 4, filtered and evaporated to leave an oil. The product was purified by flash chromatography (ethyl acetate: hexane / 50:50) to yield 48 as an oil. Compound 48 (mixture of cis and trans stereoisomers): 1 H NMR (300 MHz, CDCl 3) 6.64 (d, 2 H), 4.2 (m, 1 H), 3.85 (m, 3 H, 3.75 (s, 6 H), 3.5 (m, 1 H), 3.1 (m, 2 H), 2.8 (m, 2H), 2.55 (m, 1 H), 2.3 (m, 1 H), 1.7 8m, 3 H), 1.2 (m, 3 H).

EXAMPLE 7 Preparation of 5,8-dimethoxy-2-r / V- (L-alanyl-methyl ester) -? / - prop H -3-methyl-1,2,3,4-tetrahydronaphthalene (47) Compound 48 (0.28 g, 0.8 mmol) was dissolved in acetonitrile together with propionaldehyde (0.1 ml, 1.6 mmol, 2 equivalents) and acetic acid (0.2 ml, 1.6 mmol), and stirred 1 hour at room temperature. One hour later, sodium cyanoborohydride (0.2 g, 1.6 mmol, 2 equivalents) was added in portions (3x) over a period of 1.5 hours (every 30 minutes). The reaction was stirred overnight at room temperature. Ethyl acetate and 1 N NaOH were added to the reaction with complete mixing and the organic layer was separated, dried with MgSO 4, filtered and evaporated to leave an oil. This material was purified using flash chromatography (vaporized silica, hexane: ether / 80-20) to yield 47 (1: 1 mixture of the cis and trans steroisomers). 1 H NMR (300 MHz, CDCl 3) 6.6 (d, 2 H), 3.75 (s, 6 H), 3.7 (d, 4 H), 3.0 (m, 2 H), 2.65 (m, 3 H), 2.2 ( m, 1 H), 1.7 (m, 2 H), 1.45 (m, 2 H), 1.25 (d, 3 H), 1.0 (m, 3 H), 0.8 (t, 3 H).

EXAMPLE 8 Preparation of 5-d-phenylphosphinoyl-8-hydroxy-frans-2-di (? / - propylamino) -3-methyl-1,2,3,4-tetrahydronaphthalene (58); and 5.8-bis (diphenylphosphinoyl) -3-methyl-1, 2,3,4-tetrahydronaphthalene (59) Compound 9 (0.5 g, 2.0 mmol) was dissolved in dioxane (100 ml) at 0 ° C. Triethylamine (6 ml) was added and the reaction mixture was stirred at 0 ° C for 30 minutes, followed by the addition of diphenylphosphinyl chloride (0.84 ml, 4.4 mmol). The reaction mixture was stirred overnight at room temperature. NaHCO3 and dichloromethane were then added with complete mixing. The organic layer was separated, dried with MgSO 4, filtered, and the solvent was evaporated to leave a crude oil which was purified by flash chromatography (steamed silica, hexane: ether / 70: 30) to yield 59 and 58. Compound 59: 1 H NMR (300 MHz, CDCl 3) 7.85 (d, 4 H), 7.8 (d, 4 H), 7.5 (m, 12 H), 6.8 (q, 2 H), 3.0 (m, 2 H) , 2.4 (m, 7 H), 1.8 (m, 1 H), 1.4 (m, 4 H), 1.05 (d, 3 H), 0.85 (t, 6 H). Compound 58 (1: 1 mixture of regioisomers): 1 H NMR (300 MHz, CDCl 3) 7.85 (m, 4 H), 7.5 (m, 6 H), 6.6 (q, 1 H), 6.48 (s, 1 H) , 6.21 (d, 1 H), 2.9 (m, 3 H), 2.3 (m, 9 H), 1.65 (m, 1 H), 1.4 (m, 1 H), 1.05 (d, 3 H), 0.85 (m, 6 H). Similarly, starting from 32, compounds 57 and 56 were prepared. In addition, similarly starting from 9, compounds 49-51 were prepared using the appropriate reagents.

EXAMPLE 9 Preparation of 5,8-dimethoxy-c / s-2-W- (4- (2- (1-piperidinyl) ethoxy) phenyl) 1 amino-3-methyl-1,2.3.4-tetrahydronaphthalene (60) A solution of 1- (2-chloroethoxy) -4-nitrobenzene (2.01 g, 0.01 mole), piperidine (2.55 g, 0.03 mole) and toluene (10 ml) was refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated to give 2.97 g of 1- [2- (1-piperidinyl) ethoxy] -4-nitrobenzene as an orange oil, MS M + (m / e) 251.18. This material (1.25 g, 0.004 mol) was hydrogenated in ethanol (25 ml) in the presence of Pd 10% -C catalyst at 2.8 kg / cm2 and 25 ° C overnight. Filtration and evaporation of the reaction mixture gave 0.95 g of 4- [2- (1-piperidinyl) ethoxy] aniline as a light brown oil, MS M + (m / e) 221.24. A solution of this oil (0.220 g, 1.0 mmol), 3-methyl-5,8-dimethoxy-2-tetralone (6, 0.206, 0.94 mmol) and 1,2-dichloroethane (3.5 ml) were treated with triacetoxyborohydride. sodium (0.300 g, 1.4 mmol) and acetic acid (0.060 g, 1.0 mmol), and the resulting mixture was stirred overnight at 25 ° C. the reaction was treated with 3N sodium hydroxide solution with vigorous stirring. The organic layer was separated, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered and evaporated to leave a red oil. This material was purified by reverse phase high pressure liquid chromatography C-18, yielding compound 60 as a rose-colored solid. 1 H NMR (300 MHz, CDCl 3): 7.10-7.22 (m, 2H), 6.52-6.82 (m, 4H), 4.25-4.33 (m, 2H), 3.60-3.80 (m, 3H), 3.75 (s, 3H ), 3.71 (s, 3H), 3.48-3.38 (m, 2H), 2.80-3.05 (m, 4H), 1.80-2.10 (m, 4H), 1.10-1.50 (m, 3H), 1.00 (d, 3H) ). MS M + (m / e) 425.38. The compounds shown in Table 1 below were prepared according to the procedures described herein. 4 t »* '? ~? 'TABLE 1 Comp 'R5 Re R2 R3 Config. MS M + (m / e) 9 H H Pr Pr trans 278.24 H H Pr Pr trans, ent. 278.25 16 H H Pr Pr trans, ept. 278.21 7 Me Me 'H Pr trans 8 Me Me Pr Pr trans 306.28 17 Me Me Pr Pr trans, ent. 306.24 18 Me Me Pr Pr trans, ent. 306.27 19 Me Me Pr Ph (CH2) 3 trans 382.28 H H Pr Ph (CH2) 3 trans 354.27 21 Me Me Pr CC6rl ?? CH2 trans 360.32 22 H H Pr CC6G "II ICH trans 332.32 23 Me Me - (CH2) 2O (CH2) 2- cis 292.66 24 H H - (CH 2) 2 O (CH 2) 2- cis 264.28 Me Me Pr CH2Ph trans 354.74 26 H H Pr CH2Ph trans 326.21 27 Me Me Pr MeS (CH2) 3 trans 352.29 28 H H Pr MeS (CH2) 3 trans 324.24 29 Me Me Pr (2-thienyl) CH2 trans 360.24 H H Pr (2-thienyl) CH2 trans 332.14 31 Me Me Pr CH2CCH trans 302.21 32 H H Pr CH2CCH trans 274.16 33 Me Me Pr CH2CCH cis 302.22 34 H H Pr CH2CCH cis 274.16 Me Me Pr CH2 (4-IPh) trans 480.11 36 H H Pr CH2 (4-IPh) trans 452.14 37 Me Me Pr CH2 (4-BuOPh) trans 426.25 38 H H Pr CH2 (4-OHPh) trans 342.16 39 Me Me Pr CH2 (2-CIPh) trans 388.18 TABLE 1 (CONTINUED) Comp R5 R2 Config. MS M + (m / e) 40 H H Pr CH2 (2-CIPh) trans 360.12 41 Me Me Pr CH2 (4-MePh) trans 368.29 42 H H Pr CH2 (4-MePh) trans 340.18 43 H X Pr Pr trans 346.29 44 X H Pr Pr trans 346.30 45 Me H Pr Pr trans 292.22 46 H Me Pr Pr trans 292.22 47 Me Me Pr CH (Me) CO2Me cis and trans 350.26 48 Me Me H CH (Me) CO2Me cis and trans 308.19 49 And And Pr Pr trans 446.39 50 H and Pr Pr trans 362.26 51 and H Pr Pr trans 362.30 52 Me Me Pr Me trans 278.19 53 H H Pr Me trans 250.18 54 Me Me Pr Z trans 402.28 55 H H Pr Z trans 374.25 56 H X 'Pr CH2CCH trans 474.13 57 X 'X' Pr CH2CCH trans 674.11 58 H X 'Pr Pr trans 478.21 59 X 'X' Pr Pr trans 678.11 60 Me Me H Y cis 425.38 X = -CH2CH = CMe2 Y = -C (O) -t-Bu z = -CH2CH2CH (Me) CH l2CH2CH = CMe2 X '= = P (O) Ph2 Y '=: 4 - [(2- (1-piperidinyl) ethyl) oxy] Ph EXAMPLE 10 As a specific embodiment of an oral composition, 100 mg of compound 9 of Example 1 was formulated with enough finely divided lactose to provide a total amount of 580 to 590 mg to fill a hard gelatin capsule of size 0.

EXAMPLE 11 The union of A? and A 1-40 to nAChRs alpha-7 can be demonstrated in competitive binding experiments with -bungarotoxin SK-N-MC cell membranes were incubated with 0.5 nM of 125 l -bungarotoxin in the presence of various concentrations of A? -2 and A 1.40 at 25 ° C for 1 hour. The test mixture was filtered rapidly and the radioactivity that was retained on the filter was determined. These studies showed that both A 1.42 and A 1-40 inhibited the binding of 125 I -bungarotoxin in a concentration dependent manner with IC 50 values of 1 pM and 100 pM, respectively.

EXAMPLE 12 The binding of A 1.42 to the alpha-7 nAChRs is supported by competitive binding experiments with 125I-A 1-40 and provides a seed for amyloid deposition and thus, for the incipient formation of plaque 5 Alpha nAChRs were immobilized. 7 on trimeric SPA globules coupled with wheat germ agglutinin and were left incubating with 125 I-A-0 in the presence of various concentrations of cold A 1-40 or A? 2. The data showed that 0.1 femtoM of cold A? _42 competitively suppressed the binding, suggesting that A? _42 interacted with alpha-7 nAChRs with high affinity. However, in the presence of 10 nM cold A? -42, the total binding of 125I-A 1.40 dramatically increased to alpha-7 nAChRs. The authors of the present invention attribute this binding increase at higher concentrations, to Aβ42-induced precipitation of the A peptides on the membranes. Prolonged incubation at lower concentrations also revealed that total binding increased in reactions, even with 100 pM of cold A 1-42. In control experiments, 80 pM of 125I-A 1.40 did not bind appreciably, together with 1 pM to 1 nM of A 1.40, to 30 g of Membrane membranes of Bowes. In this way, deposition of A can occur in biological cell membranes containing nAChRs alpha-7, but it does not occur non-specifically on control membranes, suggesting that alpha-7 nAChRs can specifically seed aggregation of -amyloid in biological systems. . ? > "• * • -> EXAMPLE 13 The binding of A 1.42 to the nAChRs alpha-7 is of higher affinity than the binding of A? -4n to the nAChRs alpha-7 Alpha-7 nAChRs were allowed to interact with A 1.40 or A 1.42, and the mixture was then immunoprecipitated with anti-nAChR alpha-7 antibodies. Western analysis of the immunoprecipitated proteins identified only the presence of A? - 2, indicating that the interaction A -? - 2 / nAChR alpha-7 is strong and of high affinity. As it has already been shown that A 1.40 binds to the alpha-7 receptor, the non-detection of A? -4o in this coprecipitation experiment suggests that the interaction A? - 0 / nAChR alpha-7 is of lower affinity than the interaction A? -42 / nAChR alpha-7.

EXAMPLE 14 Compound 9 inhibited the aggregation of A It is known that A form aggregates that lead to the formation of amyloid plaques that are characteristic of Alzheimer's disease. This phenomenon can be demonstrated in vitro using Synthaloid plates, covered with crystallization centers A, and A s labeled to detect aggregation. We have validated this aggregation test using 125I-A ^ 40 and fluo-A? -40 in a buffer containing 50 mM HEPES, pH 7.4, 0.1% BSA, 10% FCS, and protease inhibitors. Approximately 500 pM of 125I-A 1.40 or 100 nM of fluo-A-0 in 100 I of each well of the 96-well Synthaloid plate was allowed to incubate for 2.5 hours at room temperature in the presence or absence of inhibitors. . At the end of the incubation, unbound protein was removed in the wells by three washes using the previous buffer. The amount of bound protein that represented the aggregation of A was measured either by scintillation counting or by fluorescence measurements. It was found that compound 9 potently inhibits aggregation A with IC50 of 10 nM. Studies on time also showed that prolonged incubation of amyloid aggregates with compound 9 resulted in disintegration. Compounds that inhibit the aggregation of A with an IC50 < 100 micromolar, can be effective to inhibit the binding of A to alpha-7, such that they have a positive therapeutic effect useful for the treatment of neurodegenerative disorders.

EXAMPLE 15 Compound 9 blogged the effect of A s on the release of acetylcholine from synaptosomes Guinea pig synaptosomes of guinea pigs were incubated with 0.1 M of 3 H-choline, and then subjected to repeated washes to remove 3H-choline not incorporated. The synaptosomes were treated with 65 mM K + for 30 seconds to produce 3H-acetylcholine release. It was found that, while A 1-40 and A? -42 to 100 pM both inhibited the acetylcholine release of these preparations (33% inhibition for both A 1-40 and A? .42), the pretreatment of synaptosomes with 10 nM of compound 9 and 100 pM of either of A 1-40 and A? _42 before stimulation with K +, has no effect on the release of acetylcholine.

EXAMPLE 16 Compound 9 inhibited the binding of 125 I-A 1.40 to the nAChRs alpha-7 To determine the effect of compound 9 on 125I-A 1-40 at nAChRs alpha-7, SK-N-MC cell membranes containing nAChR alpha-7 were immobilized on Yttrium SPA globules coupled with wheat germ agglutinin, and were left incubating with 125 I-A 1.40 in the presence of various concentrations of compound 9. The result demonstrated that compound 9 efficiently inhibited the binding of 125 I-A ^ 0 to SK-N-MC cells with an IC50 of 300 pM. Compounds that inhibit the binding of A to nAChRs alpha-7 with an IC5o < 1 micromolar, can have a positive therapeutic effect useful for the treatment of neurodegenerative disorders.

EXAMPLE 17 Test for Peptide Binding to Extension 206-216 of Human nAChR 7 An amount of 2-5 ug of the 11 amino acid peptide comprised of extension 206-216 of nAChR 7 (N-Ac, C (O) NH2), was added to a 96-well microtiter plate in 50 ml of HEPES 10. mM, pH 7.4, or any 50 ul buffer. 125l-amyloid-4o (2000 Ci / mmol, 50 pM) was added to the wells in the presence and absence of inhibitors (1 uM to 10 uM) dissolved in 1 uL of 30% or 100% DMSO. The unbound ligands were removed and the bound radioactivity was measured using a Microbeta liquid scintillation counter. The ligand binding can be inhibited by -bungarotoxin, the peptide itself and the compound 9. In the following Table 2, biological data are given for representative compounds of the present invention.

TABLE 2 Comp. % Inhibition of% Union of nAChR% release # aggregation 7 206-216 from ACh to 10 M (conc M) (Co. ,.M) 9 > 90 (10) 94 94 (0.1) 15 50-90 (10) 85 (0.25) 16 50-90 (10) 44 (10) 7 50 (100) NT NT 8 50-90 (10) NT (0.7) 17 > 90 (10) NT 63 (1) 18 50-90 (10) NT 70 (10) 19 30 (5) NT NT J || ^ g¡j & , «", * Í * i > .. t ^ > ^ TABLE 2 (CONTINUED) Comp). % Inhibition of% Union of nAChR% release # Aggregation 7206-216 from ACh to 10 M (conc M) (Cl50 > M) 39 (5) NT NT 21 20 (5) NT NT 22 38 (50) NT NT 23 NT 54 NT 24 NT 43 NT NT 48 NT 26 < 30 (10) 64 NT 27 NT NT NT 28 50-90 (10) 34 NT 29 12 (10) NT NT 38 (5) NT NT 31 34 (10) NT NT 32 69 (10) NT NT 33 NT NT NT 34 69 (10) NT NT 38 (10) NT NT 36 < 30 (10) NT NT 37 < 30 (10) NT NT 38 < 30 (10) NT NT 39 85 (10) NT NT 40 75 (10) NT NT 41 < 30 (10) 19 14 42 60 (10) NT NT 43 50-90 (10) 10 0 44 50-90 (10) 23 0 45 30-50 (78) NT 78 46 50-90 (10) 18 0 47 NT NT NT 48 < 30 (10) 2 0 49 50-90 (10) 0 17 50 < 30 (10) 0 67 51 30-50 (10) 0 54 52 60 (10) 0 0 53 50-90 (10) 0 18 54 50-90 (10) 0 0 55 50-90 (10) 0 15 56 < 30 (10) 78 8 57 < 30 (10) 63 11 58 < 30 (10) 42 18 59 < 30 (10) 72 25 60 very active 0 24 Although the foregoing specification teaches the principles of the present invention, with examples provided for purposes of illustration, it will be understood that the practice of the invention encompasses all customary variations, adaptations and / or modifications that come within the scope of the following claims and their equivalents. ^ flia ^ üfe

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. The use of a compound that inhibits the binding of an amyloid beta peptide with the nicotinic acetylcholine alpha-7 receptors for the manufacture of a medicament for the treatment of a neurodegenerative disorder in a subject.

2. The use of a compound as claimed in claim 1, wherein the nicotinic acetylcholine alfa-7 receptors are human nicotinic acetylcholine alfa-7 receptors.

3. The use of a compound as claimed in claim 2, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Pick's disease, Lewi's diffuse body disease, progressive supranuclear palsy. Steel-Richardson), multisystem degeneration (Shy-Drager syndrome), neuronal motor diseases that include amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson-Guam Dementia complex, subacute sclerosing panencephalitis, Huntington's disease, Parkinson, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease / spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette disease, bulbar and pseudobulbar palsy, spinal muscular atrophy and spinobulbar (Kennedy disease), sclerosis primary lateral, spastic paraplegia, familial disease e Werdnig-Hoffman, Kugelberg-Weiander disease, Tay-Sach disease, Sandhoff's disease, familial spastic disease, Wohlfart-Kugelberg-Weiander disease, spastic paraparesis, progressive multifocal leukoencephalopathy and prion-related diseases (including Creutzfeldt's disease) Jakob, Gerstmann-Stráussler-Scheinker, Kuru, and fatal familial insomnia), dementia associated with age, vascular dementia, diffuse gray matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, head trauma dementia and diffuse brain damage, pugilistic dementia and frontal lobe dementia; neurodegenerative disorders originating from ischemia or cerebral infarction, including embolic occlusion and thrombotic occlusion, as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, non-neuropathic hereditary amyloid, Down syndrome, macroglobulinemia, Mediterranean fever secondary family, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis arthropathy and Finnish and Iowa amyloidosis.

4. The use of a compound as claimed in claim 3, wherein the beta amyloid peptide is A ^ 2-

5. The use of a compound as claimed in claim 3, wherein the Neurodegenerative disorder is Alzheimer's disease.

6. The use of a compound as claimed in claim 5, wherein the compound inhibits the binding of A 1.42 with the human nicotinic acetylcholine receptor alpha-7, joining A? -42.

7. The use of a compound as claimed in claim 3, wherein the compound inhibits the binding of A? -42 with the human nicotinic acetylcholine alfa-7 receptor, binding to the receptors 10 nicotinic acetylcholine alfa-7 human.

8. The use of a compound as claimed in claim 3, wherein the compound inhibits A-2 binding to the human nicotinic acetylcholine alfa-7 receptor, inhibiting the aggregation of amyloid beta peptides.

9. The use of a compound as claimed in claim 5, wherein the compound is of the formula I I wherein R1 is hydrogen or C1-C4 alkyl; R 2 is selected from hydrogen, C 1 -C 6 alkyl, aryl or C 7 -C 0 aralkyl; R3 is selected from hydrogen, ^ ¿U > e * f frf * > ? * - ff 'C-C-alkyl, C3-C10-alkenyl, C3-C-cycloalkyl Ci-C' alkyl, C 1 -C 6 alkoxycarbonyl C 1 -C 6 alkyl, CrC 6 alkylthio, heteroaryl C 1 -C 4 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted C 7 -C 10 aralkyl, wherein the substituent on the aryl or aralkyl is one or more substituents independently selected from the group consisting of halogen, hydroxy, CI-CT alkyl and unsubstituted or substituted C Cß alkoxy, wherein the substituents on the alkoxy are one or more substituents independently selected from amino, C 1 -C 6 alkylamino, Ci-Cβ dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six member heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; R 4 is C 1 -C 6 alkyl, aryl, or C 7 -C 10 aralkyl; and R5 and Re are each independently selected from hydrogen, C -? - C6 alkyl, C3-C10 alkenyl, C? -C8 alkylcarbonyl, or diphenylphosphinyl; and pharmaceutically acceptable salts and prodrugs thereof.

10. The use of a compound that inhibits the binding of an amyloid beta peptide with the nicotinic acetylcholine alfa-7 receptors for the manufacture of a medicament for the treatment and / or prevention of dementia in a patient with Alzheimer's disease. 1.

The use of a compound as claimed in claim 10, wherein the beta amyloid peptide is A 1 ^ 2 and the nicotinic acetylcholine alpha-7 receptors are the human nicotinic acetylcholine alfa-7 receptors.

12. - The use of a compound as claimed in claim 11, wherein the compound is of the formula I: i wherein Ri is hydrogen or C1-C4 alkyl; R 2 is selected from hydrogen, C -Cβ alkyl, aryl or aralkyl of C -C?; R3 is selected from hydrogen, Ci-Cß alkyl, C3-C10 alkenyl, Cs-Cß cycloalkyl Ci-Cß alkyl, CrCβ alkyloxy Ci-C alquilo alkyl, C Cß alkylthio, heteroaryl-C1 alkyl -C4, unsubstituted or substituted aryl or unsubstituted or substituted C7-C-? 0 aralkyl, wherein the substituent on the aryl or aralkyl is one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci alkyl -Cβ and unsubstituted or substituted Ci-Cβ alkoxy, wherein the substituents on the alkoxy are one or more substituents independently selected from amino, Ci-Cβ alkylamino, CrC6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six member heterocyclic ring selected from pyrrolidinyl, pipepdinyl, morpholinyl, thiomorpholinyl or piperazinyl; R 4 is C 1 -C 7 alkyl, aryl, or C 7 -C 10 aralkyl; and R5 and Re are each independently selected from hydrogen, C 1 -C 7 alkyl, C 3 -C 10 alkenyl, C 1 -C 2 alkylcarbonyl, or diphenylphosphinyl; and pharmaceutically acceptable salts and prodrugs thereof.

13.- The use of a compound to inhibit the binding of a peptide beta amyloid with the nicotinic acetylcholine alfa-7 receptors for the manufacture of a medicament for improving memory and / or stopping the advance of mental deterioration, in a patient with Alzheimer's disease.

14. The use of a compound as claimed in claim 13, wherein the amyloid beta peptide is A 1.42, and the nicotinic acetylcholine alpha-7 receptors are the human nicotinic acetylcholine alpha-7 receptors.

15. - The use of a compound as claimed in claim 14, wherein the compound is of the formula I: I wherein R1 is hydrogen or CrC4 alkyl; R2 is selected from hydrogen, C 7 -C 7 alkyl, aryl or C 7 -C aralkyl; R3 is selected from hydrogen, C? -C6 alkyl, C3-C10 alkenyl, C3-C8 cycloalkyl-C? -C6 alkyl, CrC6 alkoxycarbonyl-CrC6 alkyl, C? -C6 alkylthio> < RTI ID = 0.0 > heteroaryl-C1-C4 alkyl, unsubstituted or substituted aryl or C7-C? or unsubstituted or substituted aralkyl, wherein the substituent on the aryl or aralkyl is one or more substituents independently selected from the group consisting of halogen, hydroxy , C -Cß alkyl and unsubstituted or substituted CI-CT alkoxy, wherein the substituents on the alkoxy are one or more substituents independently selected from amino, Ci-Cβ alkylamino, Ct-Cβ dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six member heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; R 4 is C 1 -C 7 alkyl, aryl, or C 7 -C 10 aralkyl; and R 5 and Re are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 10 alkenyl, C 1 -C 6 alkylcarbonyl, or diphenylphosphinyl; and pharmaceutically acceptable salts and prodrugs thereof.

16. A method for identifying compounds that are useful for the treatment of neurodegenerative disorders, including the selection of test compounds to determine their ability to block the interaction of a peptide selected from the group consisting of 125 I-A-O, A 1-40 and A? -42, with nicotinic acetylcholine receptors.

17. The method according to claim 16, further characterized in that the nicotinic acetylcholine receptors are the human nicotinic acetylcholine alpha-7, human alpha-8 and / or alpha-9 receptors.

18. The method according to claim 17, further characterized in that the nicotinic acetylcholine receptors are nicotinic acetylcholine alfa-7 human receptors.

19. The method according to claim 18, further characterized in that the peptide is 125 I-A 1-40.

20. A compound of the formula I: I wherein Ri is hydrogen or C1-C4 alkyl; R 2 is selected from hydrogen, C 1 -C 7 alkyl, aryl or C 7 -C aralkyl; R3 is selected from hydrogen, Ci-Cß alkyl, C3-C10 alkenyl, C3-cycloalkyl CI-CT alkyl, Ci-Cß alkoxycarbon Ci-Cß alkyl, d-Cß alkylthio, heteroaryl- C 1 -C 4 alkyl, unsubstituted or substituted aryl or C 7 -C aralkyl or unsubstituted or substituted, wherein the substituent on the aryl or aralkyl is one or more substituents independently selected from the group consisting of halogen, hydroxy, alkyl of Ci-Cβ and unsubstituted or substituted C 1 β alkoxy, wherein the substituents on the alkoxy are one or more substituents independently selected from amino, Ci-Cβ alkylamino, C 1 -C 6 dialkylamino, pyrrolidinyl, piperidinyl, azepinyl or morpholinyl; or R2 and R3, together with the nitrogen to which they are attached, form a five or six member heterocyclic ring selected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl; R 4 is C 1 -C 6 alkyl, aryl, or C 7 -C 10 aralkyl; and R5 and RT are each independently selected from hydrogen, C-C-alkyl, C3-C10-alkenyl, CrC8-alkylcarbonyl, or diphenyl-phosphinyl; and pharmaceutically acceptable salts and prodrugs thereof.

21. The compound according to claim 20, further characterized in that R1 is hydrogen; R2 is selected from hydrogen or C1-C4 alkyl; R3 is selected from C1-C4alkyl, C3-C10alkenyl, C5-C6cycloalkyl-C1-C4alkyl, Ci-C4alkoxycarbon C4alkyl, Ci-Cysalkylthio, heteroaryl-C1alkyl -C4, or C7-C- or unsubstituted or substituted aralkyl, wherein the substituent on the aralkyl is one or two substituents independently selected from the group consisting of halogen, hydroxy, alkyl of -04 and C1-6 alkoxy C4 unsubstituted or substituted, wherein the substituents on the alkoxy are one or two substituents independently selected from amino, C1-C4 alkylamino, dialkylamino of ^ -04, pyrrolidinyl or piperidinyl; or R2 and R3, together with the nitrogen to which they are attached, form a morpholinyl ring; R 4 is C 1 -C 4 alkyl; and R5 and Re are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 alkenyl, C-C6 alkylcarbonyl, or diphenylphosphinyl; and pharmaceutically acceptable salts and prodrugs thereof.

22. The compound according to claim 20, further characterized in that it is of the formula: wherein Ri is hydrogen or C1-C4 alkyl; R2 and R3 are each independently selected from hydrogen, C-Cß-alkyl, aryl or C7-C?-Aralkyl; and R 4 is C 7 -C 7 alkyl, aryl or C 7 -C aralkyl; and pharmaceutically acceptable salts thereof.

23. The compound according to claim 22, further characterized in that it is 5,8-dihydroxy-fraps-2-di - (? / - propylamino) -3-methyl-1, 2,3,4-tetrahydronaphthalene, and its pharmaceutically acceptable salts and prodrugs.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound as claimed in claim 20.

25.- A pharmaceutical composition that is prepared by mixing a compound as claimed in claim 20, and a vehicle pharmaceutically acceptable.

26. A process for preparing a pharmaceutical composition comprising mixing a compound as claimed in claim 20, and a pharmaceutically acceptable carrier. 27.- A method to diagnose Alzheimer's disease, monitor the progress and prognosis of Alzheimer's disease and / or monitor 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 cells circulating in the blood and / or neuroepithelial neuronal cell bodies olfactory or neuronal prolongations; and (b) analyzing the test sample for the interaction of an amyloid beta peptide with the nicotinic acetylcholine alpha-7 receptors. ^ ¡G * s me ^^ a¡ ?? i